Drugs, Health Technologies, Health Systems

Reimbursement Recommendation

Leniolisib (Joenja)

Indication: For the treatment of activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and pediatric patients 12 years of age and older

Sponsor: Pharming Technologies B.V.

Final recommendation: Reimburse with conditions

Summary

What Is the Reimbursement Recommendation for Joenja?

Canada’s Drug Agency (CDA-AMC) recommends that Joenja be reimbursed by public drug plans for the treatment of activated phosphoinositide 3-kinase delta syndrome (APDS) in adults and pediatric patients aged 12 years and older if certain conditions are met.

Why Did CDA-AMC Recommend Reimbursement?

The Canadian Drug Expert Committee (CDEC) determined that it is uncertain whether Joenja demonstrates acceptable clinical value compared with best supportive care (BSC), which includes immunoglobulin (Ig) replacement therapy (IRT), steroids, and immunomodulators, in patients with APDS. Given that Joenja is expected to be an alternative to BSC, acceptable clinical value refers to at least comparable value versus BSC.

Evidence from a clinical study showed that Joenja given for 12 weeks likely helps some immune cell populations return to normal and likely helps reduce the size of enlarged lymph nodes when compared with BSC in patients with APDS. Findings from a clinical study where treatment continued for up to 6 years showed that patients receiving Joenja may have fewer infections and use less IRT. Evidence from 3 additional studies supported the findings from the clinical studies showing a possible reduction in infections among patients receiving treatment with Joenja compared to without Joenja. There was uncertainty in the evidence supporting clinical value due to the clinical studies enrolling a small number of patients, the 12-week duration of 1 study, the focus being on end points that were not direct measures of patient-important outcomes, and the possibility of incomplete, inaccurate, or low-quality data used in the 3 supportive studies.

CDEC established that there was significant unmet clinical need due to the severity of APDS, despite available treatments, and due to challenges with evidence generation in this patient population. Joenja is the first Health Canada–approved therapy that treats the underlying cause of APDS, which BSC does not. CDEC concluded that Joenja addresses a significant unmet clinical need, despite the uncertainty in the clinical value.

Based on all of the preceding considerations, CDEC recommended that Joenja be reimbursed.

Which Patients Are Eligible for Coverage?

Joenja should only be reimbursed for patients who are aged 12 years and older, weigh 45 kg or more, have a genetically confirmed diagnosis of APDS, and have documented evidence of disease, in line with the Health Canada indication.

What Are the Conditions for Reimbursement?

Joenja should only be reimbursed if patients meet the conditions detailed in Table 1, and if the cost of Joenja is reduced. Initiation and management of therapy with Joenja should be performed by clinicians with expertise in APDS or other inborn errors of immunity. The recommended duration of initial authorization is 12 months, followed by annual renewals thereafter. Renewal is recommended to be based on an observation of clinical benefit as assessed by the treating physician.

Important budget impact considerations and organizational implications regarding genetic testing must be addressed for health systems to be able to adopt Joenja.

Review Background

Highlights of Input From Interested Parties

The patient group (Canadian Immunodeficiencies Patient Organization operating as Immunity Canada) noted the following regarding impacts of the disease, unmet needs, and important outcomes:

The clinician group (The Medical Science Advisory Committee of Immunity Canada along with representatives of the Clinical Immunology Network-Canada) and the clinical experts consulted by CDA-AMC noted the following regarding unmet needs arising from the disease and place in therapy for the drug under review:

The participating public drug programs provided input regarding considerations for initiation.

Person With Lived Experience

A person with lived experience from Ontario shared her journey living with APDS. She described experiencing recurrent infections from childhood, including frequent sinus infections, pneumonia, stomach issues, and Epstein-Barr virus infections. At 7 years old, she was diagnosed with hyper-IgM syndrome and began treatment at a children’s hospital. Her initial treatment consisted of IVIg every 3 to 4 weeks. During high school and early college, she transitioned to subcutaneous Ig (Hyzentra), which they have used for approximately 12 years, and which significantly improved immune function. In 2024, a severe respiratory illness initially thought to be pneumonia was diagnosed as pneumocystis jirovecii pneumonia, requiring a month-long hospitalization. This event prompted further genetic testing, which confirmed a diagnosis of APDS2 in January 2025 at age 28 years. Before her APDS2 diagnosis, she experienced longstanding lymphoproliferation, including persistent, enlarged lymph nodes in the neck that never received a clear explanation; had a previous cancer scare at age 22 due to abnormal lymph nodes and concerns about lymphoma; and developed splenomegaly and possible hepatomegaly, both common manifestations of APDS. She described how the APDS2 diagnosis provided explanations for many previously unexplained symptoms and clinical findings. She began treatment with leniolisib following APDS2 diagnosis and has been in treatment for approximately 1 year. Before starting treatment with leniolisib, she relied on frequent courses of antibiotics, particularly clavulin, for recurrent sinus, ear, respiratory, and gastrointestinal infections. She noted the following benefits of treatment with leniolisib: complete resolution of enlarged neck lymph nodes; significant reduction in lymphoproliferation; reduction in spleen and liver enlargement; improved laboratory markers; reduced risk factors associated with B-cell lymphoma; and overall improvement in quality of life. She stressed that leniolisib provided a clear improvement where previous treatments had not. She reported no noticeable side effects after 1 year of treatment. She continues to require monitoring for possible autoimmune complications but reported a markedly improved health status and quality of life since starting treatment. She emphasized that leniolisib should remain available as a treatment option for patients with APDS because of its transformative impact.

Note: The perspectives shared by people with lived experience who present to the committee reflect their individual experiences and are not necessarily representative of all people with the same condition or course of treatment. Their insights provide valuable context about what a patient, support person, or caregiver might go through with this condition or treatment, helping to inform the committee’s deliberations. These narratives complement other forms of evidence and input and should be considered as 1 element contributing to a broader understanding of the condition and treatment under review.

Recommendation

With a vote of 14 in favour to 0 against, CDEC recommends that leniolisib be reimbursed for the treatment of APDS in patients aged 12 years and older 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 leniolisib should be reimbursed when initiated in patients who are aged 12 years and older, weigh 45 kg or more, have a genetically confirmed diagnosis of APDS caused by a pathogenic variant in a PI3K-delta pathway gene (e.g., PIK3CD or PIK3R1 variants), and have documented evidence of disease.

Evidence from Study 2201 Part II demonstrated that when compared to placebo, treatment with leniolisib likely resulted in improvements in lymphoproliferation and/or improvements in abnormal immunological parameters in patients with these characteristics.

Weight: CDEC agreed with the clinical experts that the 70 mg, twice a day dosage of leniolisib should not be used to treat patients weighing less than 45 kg. This is aligned with the Health Canada–recommended dosage for leniolisib.

Genetic diagnosis: CDEC and the clinical experts noted that reimbursement eligibility for leniolisib should require genetic confirmation of a pathogenic APDS variant. In Study 2201 Part II, genetic confirmation was defined as a documented APDS-associated or PASLI-associated genetic PI3K-delta variant (PIK3CD or PIK3R1 variants). The examples listed in the initiation criterion (e.g., PIK3CD or PIK3R1) are not intended to exclude other pathogenic variants that may be subsequently recognized as causing APDS.

Evidence of disease: CDEC and the clinical experts agreed that there should be documented evidence of disease. It was noted that this does not need to be active disease manifestations and should not require CT or MRI evidence of nodal disease. Clinical evidence of disease can include, but is not limited to, lymphoproliferation (documented clinically or radiographically), frequent infections, or abnormal immune parameters (identified through laboratory investigations).

2. Duration of initial authorization is 12 months.

While the pivotal study duration was 12 weeks, the clinical experts noted to CDEC that response to treatment would initially be assessed at 6 months and every 12 months once stable. CDEC considered the clinical experts’ suggestion as well as challenges with accessing specialists to recommend an initial authorization duration of 12 months.

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Renewal

3. For renewal after initial authorization and subsequent renewal (every 12 months), the physician must provide proof of beneficial clinical effect when requesting continuation of reimbursement.

Evidence from Study 2201 Part II demonstrated that when compared to placebo, treatment with leniolisib likely resulted in improvements in lymphoproliferation and/or improvements in abnormal immunological parameters. This is to ensure that reimbursement is continued only for patients who demonstrate ongoing clinical benefit from treatment.

CDEC and the clinical experts noted that lymphadenopathy can be evaluated in practice through clinical assessment or ultrasound, but that frequent CT or MRI scans (as was done in Study 2201) are difficult to obtain or are avoided. They added that flow cytometry, to measure B-cell subsets, is generally accessible in tertiary care centres or samples can be sent to where testing is available.

According to clinical experts, patients who initiate treatment for APDS would be initially assessed at 6 months and every 12 months once the condition was stable.

Examples of clinical benefit may include improvement or stabilization of infection frequency, lymphoproliferation, autoimmune manifestations, abnormal immune parameters, or other clinically relevant features of APDS identified before treatment initiation.

Prescribing

4. Leniolisib must be prescribed by clinicians with expertise in managing APDS or other inborn errors of immunity, such as a clinical immunologist or a specialist functioning as an immunologist.

This is meant to ensure that leniolisib is prescribed for appropriate patients and

that adverse effects are managed in an optimized and timely manner.

CDEC and the clinical experts agreed that there are few clinical immunologists in Canada and to improve patient access to specialized care, clinicians who are part of the Clinical Immunology Network Canada may be appropriate prescribers of leniolisib. Furthermore, clinicians who have adequate training in the disease area and in consultation with an immunologist or specialist could prescribe and monitor treatment with leniolisib.

5. Leniolisib may be administered in combination with BSC for APDS.

BSC for APDS can include antimicrobials, IRT, immunomodulators, surgery, and HSCT.

CDEC and the clinical experts agreed that patients should not be required to try off-label treatments for APDS before initiating leniolisib.

CDEC and the clinical experts agreed that patients who are receiving off-label treatments for APDS would be eligible for leniolisib. The goal is to reduce or stop BSC, but it may not always be possible.

Pricing

6. A reduction in price.

Using the CDA-AMC base-case analysis, the ICER for leniolisib plus BSC was $8,570,334 per QALY gained when compared with BSC in the indicated population. A band 4 price reductiona would be required to achieve cost-effectiveness at a $50,000 per QALY threshold. A band 4 price reductiona would be required to achieve cost-effectiveness at a $100,000 per QALY threshold. Price reductions for any given willingness-to-pay threshold are available in the CDA-AMC Main Report and Supplemental Material document.

The CDA-AMC analysis is based on public list prices for all treatments. Further price reductions may be required if there are price arrangements (discounts) currently in place for any treatment included in the economic analysis. Likewise, further price reductions may be required to address economic feasibility of adoption.

Feasibility of adoption

7. The economic feasibility of adoption of leniolisib plus BSC must be addressed.

At the submitted price, the magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption, given the difference between the sponsor’s estimate and the CDA-AMC estimate.

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8. The organizational feasibility of adoption of leniolisib must be addressed regarding genetic testing for APDS.

CDEC acknowledges that the availability of genetic testing for APDS in Canada is a barrier that needs to be addressed.

CDEC noted that access to genetic testing is essential for identifying eligible patients and that testing capacity may be limited in some jurisdictions. To avoid creating additional financial and operational burdens for public health care systems, CDEC recommends that the sponsor continue to support and fund APDS genetic testing across Canada. The sponsor has indicated that no-cost genetic testing is currently available through its navigateAPDS program in partnership with a genetic testing provider.

APDS = activated phosphoinositide 3-kinase delta syndrome; BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; CDEC = Canadian Drug Expert Committee; HSCT = hematopoietic stem cell transplant; ICER = incremental cost-effectiveness ratio; IRT = immunoglobulin replacement therapy; PASLI = PI3K-p110δ activating mutation causing senescent T-cells, lymphadenopathy, and immunodeficiency; PI3K = phosphoinositide 3-kinase; QALY = quality-adjusted life-year.

aFor the statement regarding the size of the price reduction required, band 1 = 1% to 24%, band 2 = 25% to 49%, band 3 = 50% to 74%, and band 4 = 75% or greater.

Rationale for the Recommendation

Clinical Value

Based on the totality of the clinical evidence, CDEC concluded that it is uncertain whether leniolisib demonstrates acceptable clinical value compared with appropriate comparators (i.e., BSC) in patients with APDS. Given that leniolisib is expected to be an alternative to BSC, acceptable clinical value refers to at least comparable value versus BSC. However, Study 2201 Part II excluded patients with recent or concurrent use of immunosuppressive medications.

Evidence from 1 randomized controlled trial (RCT) demonstrated that treatment for 12 weeks with leniolisib likely results in added clinical benefit for patients aged 12 years and older with APDS compared with placebo in the normalization of immune parameters (e.g., naive B-cell populations) and reduced lymphoproliferation. These were evaluated using surrogate outcomes and the impact of leniolisib on clinical outcomes that are meaningful to patients is uncertain at 12 weeks. Results from 1 open-label extension (OLE) study indicated that continued treatment with leniolisib may result in fewer infections and reduced IRT use. This was based on a noncomparative study design and few patients with 6 years of follow-up data. Evidence from 1 externally-controlled study and 2 real-world evidence studies included to address gaps in the systematic review evidence suggested that the direction of effect with leniolisib is consistent with the RCT and OLE. However, there was uncertainty due to concerns with data completeness, accuracy, quality, and bias.

CDEC noted that the certainty in the clinical value of leniolisib is limited given the evidence was based on a single RCT enrolling a small number of patients (N = 31) for a short duration (12 weeks) and focused on surrogate end points, rather than patient-important outcomes. The committee acknowledged the roles that disease rarity and the ethics of reducing exposure to placebo have in the study design.

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

Considering Significant Unmet Clinical Need

CDEC established that there was significant unmet clinical need due to the rarity, severity, and progressive nature of APDS, for which there are no other Health Canada–approved treatments.

CDEC recognized that currently available therapies primarily address disease manifestations and do not directly target the underlying pathogenic pathway. Leniolisib is the first Health Canada–approved therapy that targets the underlying disease mechanism of APDS. Evidence suggests that leniolisib potentially improves lymphoproliferation and immunological parameters associated with APDS and may reduce infections over time. However, uncertainty remains regarding the extent to which these improvements translate into reductions in infections and hospitalizations, improvements in HRQoL, and long-term control of disease manifestations. Therefore, CDEC concluded that leniolisib addresses a significant unmet clinical need to a degree that justifies a positive recommendation despite the uncertainty in the clinical value.

Further information on the committee’s discussion around unmet clinical need is provided in the Summary of Deliberation section.

Developing the Recommendation

Due to the uncertainty in clinical value, CDEC could not recommend whether to reimburse leniolisib based on clinical value alone. Therefore, they also considered whether leniolisib addresses a significant unmet clinical need. CDEC concluded that leniolisib addresses a significant unmet clinical need with an acceptable level of certainty. Based on the preceding considerations, CDEC recommended that leniolisib be reimbursed. As part of the deliberation on whether to recommend reimbursement or not, the committee also considered unmet nonclinical need and health inequity. Information on this discussion is provided in the Distinct Social and Ethical Considerations domain in the Summary of Deliberation section.

Because CDEC recommended that leniolisib be reimbursed, the committee also deliberated on whether reimbursement conditions should be added to address important economic considerations, health system impacts, or 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 considered the following information (links to the full documents for the review can be found on the project webpage):

Special thanks: CDA-AMC extends our special thanks to the individuals who presented directly to CDEC and to the patient organizations representing the community of those living with APDS, including Immunity Canada.

General note: CDA-AMC makes every attempt to engage with people with lived experience as closely to the indication under review as possible; however, at times, CDA-AMC is unable to do so and instead engages with individuals with similar treatment journeys to ensure lived experience perspectives are included and considered in Reimbursement Reviews. CDA-AMC is fortunate to be able to engage with individuals who are willing to share their treatment journeys with CDEC.

All feedback received in response to the draft recommendation is available on the CDA-AMC 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, 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: August 27, 2026

Regrets: Two expert committee members did not attend.

Conflicts of interest: None