Leniolisib for Primary Immunodeficiency

Recruiting in Palo Alto (17 mi)

Overseen by Gulbu Uzel, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Pharming Technologies B.V.

Must not be taking: Immunosuppressants, Corticosteroids, Investigational drugs, others

Disqualifiers: HIV, Hepatitis B/C, Lymphoma, others

No Placebo Group

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This study is an exploratory, non-randomized, open-label, within-patient dose escalation study. The primary objective is to assess safety and tolerability of leniolisib. Secondary objectives include assessments of PK/PD, and to explore clinical efficacy measures with administration of three different dose levels of leniolisib.

Do I need to stop my current medications to join the trial?

You may need to stop certain medications before joining the trial. Specifically, you cannot use certain immunosuppressive medications, strong inhibitors or inducers of specific enzymes, or medications that act on certain transport proteins close to the time of starting the trial. If you are on abatacept, you can continue if your dose has been stable for over 3 months.

What data supports the effectiveness of the drug leniolisib for primary immunodeficiency?

Leniolisib has been shown to be effective in treating activated PI3Kδ syndrome (APDS), a type of primary immunodeficiency, by reducing lymph node size and increasing the percentage of certain immune cells, which indicates improved immune function. In clinical trials, patients taking leniolisib experienced significant improvements compared to those taking a placebo, with fewer side effects. ^{1 2 3 4 5}

Is leniolisib safe for humans?

Leniolisib has been tested in a clinical trial for a condition called activated PI3Kδ syndrome (APDS), and it was generally well tolerated by participants. Fewer people taking leniolisib reported mild side effects compared to those taking a placebo, and it did not cause severe immune-related side effects seen with similar drugs. ^{1 2 3 6 7}

How is the drug leniolisib unique for treating primary immunodeficiency?

Leniolisib is unique because it is an oral drug that specifically targets the PI3Kδ pathway, which is crucial for immune cell function, and it has shown both efficacy and tolerability in treating activated PI3Kδ syndrome (APDS), a type of primary immunodeficiency. Unlike other similar drugs, leniolisib selectively inhibits the δ isoform without causing severe immune-related side effects. ^{1 2 3 7 8}

Research Team

Gulbu Uzel, M.D.

Principal Investigator

National Institutes of Health (NIH)

Eligibility Criteria

This trial is for people aged 12-75 with Primary Immunodeficiency (PID) who have certain blood issues, enlarged spleen or lymph nodes, specific blood pressure and heart rate ranges, lung disease related to PID, and genetic mutations linked to PID. It's not suitable for those with conditions that could explain their symptoms like iron-deficiency.

Inclusion Criteria

I am between 12 and 75 years old.

Subjects or their legal representatives must be able to provide written informed consent

I have one or more of the following: low blood counts, enlarged spleen, swollen lymph nodes, or specific lung diseases with visible changes on a chest CT.

Exclusion Criteria

Receiving concurrent treatment with another investigational therapy

I have successfully undergone a stem-cell transplant.

I have used certain medications that suppress my immune system.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive leniolisib with a dose escalation regimen: 10 mg BID for 4 weeks, 30 mg BID for 4 weeks, and 70 mg BID for 12 weeks

20 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with the EOS visit planned approximately 28 days after the last dose

4 weeks

Treatment Details

Interventions

• Leniolisib (PI3K Inhibitor)

Trial Overview The study tests Leniolisib at three different doses in patients with immune dysregulation due to PIDs. It's an open-label trial where everyone knows what treatment they're getting. The main goal is safety; other goals include how the body processes the drug and its effectiveness.

Participant Groups

Group I: Leniolisib Experimental Treatment 1 Intervention

All subjects participating will receive Leniolisib film-coated tablets (FCTs) at a starting dose of 10 mg BID for 4 weeks, followed by 30 mg BID for 4 weeks, and then 70 mg BID for 12 weeks.

Who Is Running the Clinical Trial?

Pharming Technologies B.V.

Lead Sponsor

Trials

23

Recruited

1,400+

Aixial Group

Collaborator

Trials

4

Recruited

90+

Aixial Group

Industry Sponsor

Trials

4

Recruited

90+

Findings from Research

Leniolisib (JOENJA®) is an oral medication that selectively inhibits the PI3Kδ enzyme and has been approved for treating activated PI3Kδ syndrome (APDS) in patients aged 12 and older, marking a significant advancement in immunodeficiency treatment.

The drug is currently under review in the European Union for the same indication, although its development for Sjögren's syndrome has been discontinued.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leniolisib: First Approval. Duggan, S., Al-Salama, ZT.[2023]

In a study of 72 patients with early-onset primary immunodeficiency (PID), 34.72% were diagnosed with PID disorders, and a significant 26.39% faced mortality within 180 days, highlighting the critical need for timely diagnosis and intervention.

The research identified a subgroup of patients with JAK-STAT pathway defects, where early onset (within 3.5 days) was linked to higher mortality rates, suggesting that targeted therapies based on molecular defects could improve outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary immunodeficiency-related genes in neonatal intensive care unit patients with various genetic immune abnormalities: a multicentre study in China. Zhu, T., Gong, X., Bei, F., et al.[2022]

In a phase 3 trial involving 31 patients with Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS), the oral drug leniolisib significantly reduced lymph node size and increased the percentage of naïve B cells, indicating improved immune function.

Leniolisib was well tolerated, with fewer treatment-related adverse events reported compared to placebo, suggesting it is a safe and effective option for managing immune dysregulation in APDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Rao, VK., Webster, S., Šedivá, A., et al.[2023]

The median diagnostic delay for adult patients with Common Variable Immunodeficiency (CVID) in Poland has improved to 6 years, down from an average of 10 years reported previously, especially for those with symptoms starting after 1999.

Patients with a longer diagnostic delay (over 6 years) experienced significantly more severe health issues, including higher rates of lower respiratory infections, cytopenias, granulomatous lesions, and solid tumors, highlighting the importance of timely diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shorter Diagnostic Delay in Polish Adult Patients With Common Variable Immunodeficiency and Symptom Onset After 1999. Ziętkiewicz, M., Więsik-Szewczyk, E., Matyja-Bednarczyk, A., et al.[2021]

In a clinical trial involving 6 patients with activated PI3Kδ syndrome (APDS), the selective PI3Kδ inhibitor leniolisib demonstrated a dose-dependent reduction in immune dysregulation and normalization of B cell populations after 12 weeks of treatment.

Leniolisib was well tolerated and led to significant reductions in lymph node and spleen sizes (39% and 40% respectively), indicating its potential as a targeted therapy for APDS and similar conditions characterized by PI3Kδ pathway overactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. Rao, VK., Webster, S., Dalm, VASH., et al.[2021]

Leniolisib is the only PI3Kδ inhibitor that has demonstrated both efficacy and tolerability for treating activated phosphoinositide 3-kinase δ syndrome (APDS), a genetic condition affecting immune function.

Unlike other PI3Kδ inhibitors that can cause severe side effects like colitis and neutropenia, leniolisib selectively targets the δ isoform without affecting the δ or γ isoforms, making it a safer option for patients with APDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond. Cant, AJ., Chandra, A., Munro, E., et al.[2023]

In a Phase I study with 15 healthy volunteers, the inhibition of P-glycoprotein (P-gp) by single-dose rifampicin increased the exposure of lenvatinib by approximately 32% for free and 31% for total concentrations, suggesting that P-gp plays a role in lenvatinib pharmacokinetics.

Conversely, multiple-dose rifampicin, which induces both P-gp and CYP3A4, decreased lenvatinib exposure by 18% for total and 9% for free concentrations, but these changes were small and likely not clinically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. Shumaker, RC., Aluri, J., Fan, J., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Leniolisib: First Approval. [2023]

2. Australia pubmed.ncbi.nlm.nih.gov

Primary immunodeficiency-related genes in neonatal intensive care unit patients with various genetic immune abnormalities: a multicentre study in China. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Shorter Diagnostic Delay in Polish Adult Patients With Common Variable Immunodeficiency and Symptom Onset After 1999. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Duvelisib for the treatment of chronic lymphocytic leukemia. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. [2021]