Leniolisib for Primary Immunodeficiency

Overseen By Gulbu Uzel, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Pharming Technologies B.V.

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

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 20 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of leniolisib, a new treatment for primary immunodeficiency (PID), a condition where the immune system doesn't function properly. Participants will receive increasing doses of leniolisib over several weeks to assess tolerance and symptom improvement. Suitable candidates have certain genetic types of PID and experience issues like low blood cell counts or enlarged organs. The study is open to those who have not had a successful stem-cell transplant and aren't currently using strong immune-suppressing drugs.

As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important findings.

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.

Is there any evidence suggesting that leniolisib is likely to be safe for humans?

Research has shown that leniolisib has been safe in previous studies. In one study, participants tolerated leniolisib well compared to a placebo, with no major issues reported, and the treatment met its safety goals. Another study found that leniolisib was generally well-tolerated, with no serious side effects during regular check-ups.

It is important to remember that leniolisib is being tested to ensure its safety and effectiveness for new uses. While the current study examines different doses, past research suggests that leniolisib is likely safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Leniolisib is unique because it targets a specific pathway involved in primary immunodeficiency. Unlike traditional treatments that might focus on general immune support, Leniolisib specifically inhibits the PI3Kδ pathway, which plays a crucial role in immune cell function. This targeted approach could potentially offer more precise management of the condition with fewer side effects. Researchers are excited about Leniolisib because it represents a novel way to modulate the immune system, potentially leading to more effective and safer treatment options for patients with primary immunodeficiency.

What evidence suggests that leniolisib might be an effective treatment for primary immunodeficiency?

Research has shown that leniolisib, which participants in this trial will receive, can help reduce infections in people with primary immunodeficiency. In previous studies, individuals who took leniolisib experienced fewer infections, even if they frequently got sick before. One study found that leniolisib decreased the number of respiratory infections over time. These results suggest that leniolisib could be helpful in managing primary immunodeficiency by lowering the risk of infections. ^{1 2 6 7 8}

Who Is on the Research Team?

Gulbu Uzel, M.D.

Principal Investigator

National Institutes of Health (NIH)

Are You a Good Fit for This Trial?

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

At screening, vital signs must meet specific criteria

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Leniolisib

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.

How Is the Trial Designed?

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.

Leniolisib is already approved in United States for the following indications:

Approved in United States as Joenja for:

• Activated phosphoinositide 3-kinase delta syndrome (APDS)

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+

Published Research Related to This Trial

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 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]

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]

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 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]

Duvelisib, an oral dual PI3K-delta/gamma inhibitor, has shown superior progression-free survival in patients with chronic lymphocytic leukemia (CLL) compared to the standard treatment of ofatumumab, highlighting its efficacy as a new treatment option.

Despite its high efficacy, duvelisib is associated with significant adverse events that may lead to treatment interruptions, necessitating careful management strategies such as dose adjustments and supportive care to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib for the treatment of chronic lymphocytic leukemia. Frustaci, AM., Tedeschi, A., Deodato, M., et al.[2022]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39673396

Comparative efficacy of leniolisib (CDZ173) versus ... This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06549114

NCT06549114 | Leniolisib for Immune Dysregulation in PIDs This study is an exploratory, non-randomized, open-label, within-patient dose escalation study. The primary objective is to assess safety and tolerability ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S108112062500626X

r205 effectiveness of leniolisib in reducing infections ... Treatment with leniolisib consistently demonstrated significant reductions in infection rates, regardless of patients' infection history. These results align ...

4. joenja-hcp.com joenja-hcp.com/clinical-trial/

Joenja® (leniolisib) Clinical Study Data - APDS treatment Clinical Data. Joenja demonstrated significant efficacy, safety, and tolerability in. Phase 3, randomized controlled clinical trial.1.

5. academic.oup.com academic.oup.com/cei/article/219/1/uxae107/7914686

Comparative efficacy of leniolisib (CDZ173) versus standard ... This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10841669/

Interim Analysis: Open-Label Extension Study of Leniolisib for ... The OLE's primary endpoints are all safety parameters, including reported AEs and data collected via routine physical examinations, vital ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1521661624005096

A randomised, placebo-controlled, phase III trial of ... In a 12-week phase III randomised placebo-controlled trial, leniolisib, a selective PI3Kδ inhibitor, was well-tolerated and met both co-primary endpoints.

8. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/EOCCO-leniolisib-Joenja-Policy.pdf

leniolisib (Joenja™) The real-world safety profile of leniolisib (Joenja) remains undetermined. XV. Due to the lack of long-term efficacy data, and the low confidence in the ...