Iptacopan for Paroxysmal Nocturnal Hemoglobinuria

(APPULSE Trial)

Recruiting at 42 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Anti-C5 antibodies

Must not be taking: Investigational drugs

Disqualifiers: Transplantation, HIV, Cancer, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called iptacopan in adults with a blood disorder called PNH. It aims to see if iptacopan is safe and effective. Iptacopan works by stopping the immune system from attacking red blood cells. The medication has shown significant improvement in hemoglobin levels and reduction in hemolysis.

Do I have to stop taking my current medications for the trial?

Yes, you will need to stop your current treatment with eculizumab or ravulizumab to switch to the study treatment, iptacopan.

What data supports the effectiveness of the drug Iptacopan for treating paroxysmal nocturnal hemoglobinuria?

The research on Danicopan, a similar drug that inhibits a part of the immune system called the complement pathway, shows it can reduce the breakdown of red blood cells in patients with paroxysmal nocturnal hemoglobinuria. This suggests that Iptacopan, which may work in a similar way, could also be effective for this condition. ^{1 2 3 4 5}

Is Iptacopan safe for human use?

The safety of Iptacopan, also known as Fabhalta or LNP023, has not been directly addressed in the provided research articles. However, lipid nanoparticles (LNPs), which are used in its formulation, have been used safely in other drugs like mRNA vaccines and siRNA therapies, suggesting a potential for safe use in humans. ^{6 7 8 9 10}

What makes the drug iptacopan unique for treating paroxysmal nocturnal hemoglobinuria?

Iptacopan is unique because it is an oral medication that specifically inhibits complement factor B, offering a new approach to treating paroxysmal nocturnal hemoglobinuria by targeting the alternative complement pathway, unlike existing treatments that require intravenous administration and target different parts of the complement system. ^{11 12 13 14 15}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

Adults over 18 with Paroxysmal Nocturnal Hemoglobinuria (PNH) who've been on a stable anti-C5 antibody treatment for at least 6 months can join. They must not have HIV, be pregnant, or have had recent infections or transfusions. Vaccinations against certain infections are required before starting the trial.

Inclusion Criteria

I have been on a stable dose of eculizumab or ravulizumab for at least 6 months.

I am 18 or older and have been diagnosed with PNH by my doctor.

I have been vaccinated against meningitis and pneumonia before starting iptacopan.

Exclusion Criteria

I have had cancer in any part of my body in the last 5 years.

Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial.

I have had a stem cell or solid organ transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Up to 8 weeks

Treatment

Participants receive iptacopan treatment for 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Roll-over extension

Participants who benefit from iptacopan treatment may join the Roll-over extension study

Treatment Details

Interventions

• Iptacopan

Trial Overview The trial is testing iptacopan's effectiveness and safety in PNH patients switching from their current treatments (eculizumab/ravulizumab) to iptacopan. It's an open-label study where all participants receive iptacopan for 24 weeks.

Participant Groups

Group I: Iptacopan treatment in adult PNH patients Experimental Treatment 1 Intervention

Subjects will receive iptacopan at a dose of 200 mg b.i.d. orally

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

Approved in United States as Fabhalta for:

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Primary immunoglobulin A nephropathy (IgAN)

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

In a study involving 54 HIV-infected children, the use of generic adult tablets of lopinavir/ritonavir (LPV/r) was effective, with all participants achieving a minimum trough serum concentration above the therapeutic threshold.

The median LPV trough concentration was 6.7 mg/L, with 96% of the children exceeding 4.0 mg/L, indicating that adult formulations can be safely and effectively used to treat pediatric patients when necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic drug monitoring of lopinavir in human immunodeficiency virus-infected children receiving adult tablets. Puthanakit, T., Chokephaibulkit, K., Suntarattiwong, P., et al.[2013]

In a phase 2 trial involving 10 untreated patients with paroxysmal nocturnal hemoglobinuria (PNH), danicopan, an oral complement factor D inhibitor, significantly reduced intravascular hemolysis as indicated by a decrease in lactate dehydrogenase (LDH) levels from 5.7 times the upper limit of normal at baseline to 1.8 times at day 28.

The treatment was generally well-tolerated, with only one serious adverse event reported, which resolved without lasting effects, suggesting that danicopan may be a safe option for managing hemolysis in PNH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria Risitano, AM., Kulasekararaj, AG., Lee, JW., et al.[2021]

In a retrospective analysis of 1286 patients switched to second-line therapy, both boosted atazanavir (ATV/r) and lopinavir/ritonavir (LPV/r) showed similar efficacy in increasing CD4 counts and achieving undetectable viral loads, indicating that both treatments are effective options for patients failing first-line therapy in sub-Saharan Africa.

Despite the lack of routine viral load testing, the study found that 71.2% of patients on LPV/r and 84.2% on ATV/r achieved undetectable viral loads within the first 12 months, suggesting that both therapies can be effective in managing HIV in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Boosted lopinavir vs boosted atazanavir in patients failing a NNRTI first line regimen in an urban clinic in Kampala. Laker, E., Mambule, I., Nalwanga, D., et al.[2018]

Pepstatin is an effective antimalarial compound, but its bioavailability is low, making it less effective in treating malaria caused by Plasmodium falciparum.

The enzyme PfPARE is crucial for activating esterified forms of pepstatin, and mutations in this enzyme can lead to resistance against pepstatin and other antimalarial drugs, highlighting a potential mechanism of resistance in malaria treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esterase mutation is a mechanism of resistance to antimalarial compounds. Istvan, ES., Mallari, JP., Corey, VC., et al.[2018]

A new fixed-dose combination (FDC) of Lopinavir/ritonavir (LPV/r) with nucleoside reverse transcriptase inhibitors has been developed to improve treatment adherence in children, with optimal dosing ratios established for various weight bands.

Population pharmacokinetic analyses showed that the recommended dosages effectively reached LPV efficacy targets while minimizing the risk of high ZDV concentrations that could lead to neutropenia, ensuring safer treatment options for children weighing between 4 to 25 kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations. Bouazza, N., Foissac, F., Fauchet, F., et al.[2018]

In a study using induced pluripotent stem cells (iPSCs) from Diamond Blackfan Anemia (DBA) patients, eltrombopag was found to significantly enhance erythroid maturation, suggesting it could be an effective treatment for anemia associated with DBA.

The mechanism of action for eltrombopag involves its ability to chelate excess intracellular iron, which is linked to the toxic effects of free heme, thereby improving red blood cell production in DBA models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia. Qanash, H., Li, Y., Smith, RH., et al.[2023]

Intravenously administered lipid nanoparticles (LNPs), such as patisiran and mRNA-1944, show prolonged blood circulation and can remain detectable in the body for over 28 days after a single dose, indicating their potential for sustained therapeutic effects.

Both patisiran and mRNA-1944 exhibit similar pharmacokinetic profiles, which could inform the development of future LNP-based drug delivery systems, especially in comparison to the more commonly studied intramuscularly administered LNPs like mRNA vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles. Suzuki, Y., Katsurada, Y., Hyodo, K.[2023]

Lipid nanoparticle (LNP) formulated mRNA vaccines have proven effective against SARS-CoV-2, showcasing the advantages of mRNA technology, such as rapid engineering and efficient manufacturing.

While LNP-mRNA vaccines are immunogenic and beneficial for vaccination, careful management of immune activation is essential for therapeutic uses, especially in protein replacement therapies that require long-term administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety. Vlatkovic, I.[2021]

Lipid nanoparticles (LNPs) have emerged as a revolutionary delivery system for nucleic acid therapeutics, enabling the successful clinical application of RNA-based drugs, including the first approved siRNA drug, Patisiran, in 2018.

LNPs played a crucial role in the rapid development of two mRNA COVID-19 vaccines, Comirnaty and Spikevax, highlighting their effectiveness in delivering genetic material safely and efficiently to target cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. Suzuki, Y., Ishihara, H.[2023]

Lipid nanoparticles (LNPs) can be specifically modified to target hematopoietic progenitor cells in the bone marrow, improving their uptake and delivery of siRNA to leukemia cells compared to non-targeted LNPs.

The modified LNPs showed significantly enhanced accumulation and retention in the bone marrow, suggesting they could be effective for treating leukemia and other blood disorders by targeting leukemic stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles. Swart, LE., Fens, MHAM., van Oort, A., et al.[2023]

In a phase 2 study involving 13 patients with paroxysmal nocturnal hemoglobinuria (PNH), iptacopan demonstrated significant efficacy, with 12 out of 12 evaluable patients achieving a reduction in serum lactate dehydrogenase (LDH) levels by at least 60% by week 12, indicating effective control of hemolysis.

Iptacopan was well tolerated with no severe adverse events reported, and most patients experienced clinically meaningful improvements in hemoglobin levels, remaining transfusion-free for up to 12 weeks, showcasing its potential as a safe and effective monotherapy for treatment-naïve PNH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Jang, JH., Wong, L., Ko, BS., et al.[2022]

Iptacopan, a first-in-class oral complement inhibitor, showed a 71% absorption rate in healthy volunteers, with a peak concentration reached in 1.5 hours and a half-life of 12.3 hours, indicating effective systemic availability for therapeutic use.

The drug is primarily eliminated through hepatic metabolism, with the main pathways involving CYP2C8 and UGT1A1, suggesting a low risk associated with its metabolites based on toxicology studies in rats and dogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. James, AD., Kulmatycki, K., Poller, B., et al.[2023]

In a phase 2 study involving 10 adult patients with paroxysmal nocturnal hemoglobinuria who had active hemolysis despite anti-C5 therapy, the complement factor B inhibitor iptacopan significantly reduced lactate dehydrogenase levels and improved hemoglobin concentrations after 13 weeks of treatment.

Iptacopan was well tolerated with no major drug-related safety issues, and its benefits in reducing hemolysis were maintained beyond the study period, suggesting potential for further testing as a monotherapy in larger populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Risitano, AM., Röth, A., Soret, J., et al.[2021]

Iptacopan (LNP023) is a promising oral treatment for atypical hemolytic uremic syndrome (aHUS), showing potential for effective complement inhibition and convenience compared to current intravenous therapies.

The ongoing Phase 3 study (APPELHUS) will evaluate the safety and efficacy of iptacopan in 50 patients with aHUS, focusing on achieving a complete response to thrombotic microangiopathy without the need for plasma exchange or anti-C5 therapy over 26 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. Kavanagh, D., Greenbaum, LA., Bagga, A., et al.[2023]

In a real-world study involving 61 patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan for an average of 1.3 to 14.8 months, there was a significant increase in hemoglobin levels by 2.5 g/dL and a 27.4% reduction in patients with elevated lactate dehydrogenase (LDH) levels, indicating effective treatment outcomes.

Patient and physician satisfaction with pegcetacoplan was over 90%, and both groups reported improvements in fatigue and health-related quality of life (HRQoL), suggesting that pegcetacoplan may be a preferred option compared to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity. Wilson, K., Rich, C., Hakimi, Z., et al.[2023]

References

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

Therapeutic drug monitoring of lopinavir in human immunodeficiency virus-infected children receiving adult tablets. [2013]

2. Italy pubmed.ncbi.nlm.nih.gov

Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Boosted lopinavir vs boosted atazanavir in patients failing a NNRTI first line regimen in an urban clinic in Kampala. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Esterase mutation is a mechanism of resistance to antimalarial compounds. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia. [2023]

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

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles. [2023]

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

Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. [2022]

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

Absorption, Distribution, Metabolism, and Excretion of [14C]iptacopan in Healthy Male Volunteers and in In Vivo and In Vitro Studies. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. [2021]

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

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome. [2023]

15. England pubmed.ncbi.nlm.nih.gov

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity. [2023]