Iptacopan for Paroxysmal Nocturnal Hemoglobinuria

Not currently recruiting at 83 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Iptacopan

Disqualifiers: Active infections, Malignancy, Transplantation, 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: 60 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the long-term safety and effectiveness of iptacopan, a new oral treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare blood disorder that causes premature breakdown of red blood cells. It targets individuals who previously participated in iptacopan studies and found it beneficial. Participants must have been stable on this treatment for at least three months and received specific vaccines. The trial aims to evaluate iptacopan's long-term effectiveness and facilitate its ongoing use. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to help make iptacopan widely available.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you must have been stable on iptacopan monotherapy for at least 3 months to participate.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since participants must have been stable on iptacopan alone for at least 3 months, it suggests that other medications might not be allowed.

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

Research has shown that iptacopan is generally safe for people with paroxysmal nocturnal hemoglobinuria (PNH). Studies have found that taking iptacopan as a single oral treatment can improve PNH symptoms, such as increasing hemoglobin levels and reducing the breakdown of red blood cells. Trials demonstrated these benefits without major safety issues.

While any treatment can have side effects, current data suggest that iptacopan does not cause serious problems. For those considering joining a clinical trial, this treatment appears promising in terms of safety and effectiveness based on past research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PNH?

Iptacopan is unique because it targets a different part of the disease process in paroxysmal nocturnal hemoglobinuria (PNH) compared to standard treatments like eculizumab or ravulizumab. While most treatments for PNH work by inhibiting the C5 component of the complement system, iptacopan inhibits factor B, which is part of the alternative complement pathway. This potentially allows for a more complete control of the disease and could reduce the need for regular intravenous infusions, as iptacopan is administered orally. Researchers are excited about iptacopan because it might offer a more convenient and effective treatment option for patients with PNH.

What evidence suggests that iptacopan might be an effective treatment for PNH?

Research has shown that iptacopan, a new type of medication, holds promise in treating paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder. In earlier studies, iptacopan increased hemoglobin levels, which are crucial for reducing anemia, a condition characterized by insufficient healthy red blood cells. It also reduced the breakdown of red blood cells, a major issue in PNH. Patients who switched from other treatments to iptacopan experienced better and longer-lasting results. These findings suggest that iptacopan could be a more effective treatment option for people with PNH. Participants in this trial will receive open-label oral iptacopan 200 mg b.i.d monotherapy to further evaluate its effectiveness. ^{2 4 6 7 8}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults over 18 with Paroxysmal Nocturnal Hemoglobinuria (PNH) who've been stable on iptacopan for at least 3 months after completing certain Phase 2 or 3 trials. They must have had vaccinations against specific infections. Those with recurrent invasive infections, serious health conditions that could increase risk, or a history of stem cell transplantation cannot join.

Inclusion Criteria

I have been vaccinated against meningitis, pneumonia, and Haemophilus influenzae.

I am over 18 and have finished specific iptacopan study phases for PNH without reducing dosage.

I've been stable on iptacopan alone for 3+ months and it's still beneficial.

Exclusion Criteria

I have had a bone marrow transplant.

Any comorbidity or medical condition (including but not limited to any active systemic bacterial, viral or fungal infection or malignancy) that, in the opinion of the investigator, could put the subject at increased risk or potentially confound study data.

I have had repeated serious infections like meningitis or pneumonia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive open-label oral iptacopan 200 mg b.i.d monotherapy

60 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Long-term safety, tolerability, and efficacy of iptacopan are evaluated

60 months

What Are the Treatments Tested in This Trial?

Interventions

• Iptacopan

Trial Overview The study tests the long-term safety and effectiveness of iptacopan in PNH patients. It's an open-label, single-arm extension study providing continued access to iptacopan for those who completed prior Novartis-sponsored studies.

How Is the Trial Designed?

Group I: Iptacopan Experimental Treatment 1 Intervention

Participants will be receiving open label oral iptacopan 200 mg b.i.d monotherapy

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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 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]

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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40447351/

Oral iptacopan monotherapy in paroxysmal nocturnal ... The factor B inhibitor iptacopan improved 24-week outcomes in adult patients with paroxysmal nocturnal haemoglobinuria in the phase 3 APPLY-PNH and APPOINT-PNH ...

2. novartis.com novartis.com/news/media-releases/new-phase-iiib-data-shows-novartis-fabhalta-improved-hemoglobin-levels-adult-patients-paroxysmal-nocturnal-hemoglobinuria-who-switched-from-anti-c5-therapy

New Phase IIIB data shows Novartis Fabhalta® improved ... In the Phase IIIB APPULSE-PNH study, oral Fabhalta® (iptacopan) improved the average hemoglobin (Hb) level versus baseline in adult patients ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39323666/

Iptacopan Efficacy and Safety to Treat Paroxysmal ... Iptacopan's effectiveness in improving hemoglobin levels and lowering hemolysis in PNH, both as a monotherapy and in combination with usual treatment.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04558918

NCT04558918 | Study of Efficacy and Safety of Twice Daily ... Patient-Reported Meaningful Change in Symptoms and Impacts of Paroxysmal Nocturnal Hemoglobinuria (PNH) in Three Phase III Clinical Trials of Iptacopan.

5. hematologyadvisor.com hematologyadvisor.com/news/pnh-iptacopan-yield-greater-response-c5-inhibitors-treatment-risk/

Iptacopan May Yield Greater Response Than C5 Inhibitors ... Our results indicate that adult patients with PNH who have not received C5 inhibitor therapy may experience greater and sustained improvements ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S235230262500081X

Oral iptacopan monotherapy in paroxysmal nocturnal ... The factor B inhibitor iptacopan improved 24-week outcomes in adult patients with paroxysmal nocturnal haemoglobinuria in the phase 3 APPLY-PNH and APPOINT-PNH ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04747613

Study Details | NCT04747613 | Long-term Safety and ... This study is an open-label, single arm, multicenter, roll-over extension study to characterize long-term safety, tolerability and efficacy of iptacopan.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2023/218276Orig1s000IntegratedR.pdf

218276Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov hour; NVP-LNP023, Novartis Pharmaceuticals iptacopan; PNH, paroxysmal nocturnal hemoglobinuria. Results suggest that iptacopan suppress intravascular and ...