Iptacopan for Atypical Hemolytic Uremic Syndrome

(APPELHUS Trial)

Recruiting at 95 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must not be taking: Complement inhibitors

Disqualifiers: ADAMTS13 deficiency, Transplantation, Sepsis, 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: 26 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests iptacopan (also known as Fabhalta, LNP023, LNP-023, NVP-LNP023, or NVP-LNP023-NX) to determine its effectiveness and safety for people with aHUS, a condition where blood clotting leads to kidney problems and other issues. The trial targets patients who have not yet received complement inhibitor therapy, a common treatment for aHUS. Participants should be adults with active symptoms such as low platelets, signs of blood cell breakdown, and kidney troubles. As a Phase 3 trial, this is the final step before FDA approval, offering participants a chance to contribute to the availability of a new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on complement inhibitors or have certain conditions like ADAMTS13 deficiency. It's best to discuss your specific medications with the trial team.

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

Research has shown that iptacopan is generally safe for people. Previous studies on patients with conditions like Paroxysmal Nocturnal Hemoglobinuria found that iptacopan did not harm the immune system, suggesting its safety. Those studies noted no specific side effects, which is promising. As this treatment is in Phase 3 trials, it has already demonstrated some safety in earlier research stages. However, individual experiences may vary, so discussing potential risks with a doctor is important. ^{1 2 3 4 5}

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

Iptacopan is unique because it targets a specific part of the immune system called the alternative complement pathway, which is a new approach for treating atypical hemolytic uremic syndrome (aHUS). Unlike standard treatments that often involve plasma exchange or the use of C5 inhibitors like eculizumab, iptacopan directly inhibits factor B, a component of the complement system. This targeted mechanism not only offers a novel way of managing aHUS but also has the potential to be more convenient, as it is taken orally, whereas current options are typically intravenous. Researchers are excited about iptacopan because it might provide a more effective and easier-to-administer option for patients.

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

Research has shown that iptacopan might help treat atypical Hemolytic Uremic Syndrome (aHUS), a condition where abnormal blood clotting can damage organs like the kidneys. Iptacopan blocks a protein that contributes to this harmful process. Early results suggest that iptacopan can reduce these dangerous blood clots. Although more information is needed, the treatment appears promising based on its targeted approach to the disease. Participants in this trial will receive iptacopan in a single-arm open-label study to further evaluate its effectiveness. ^{1 2 3 5 6}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

Adults with atypical Hemolytic Uremic Syndrome (aHUS) who haven't been treated with complement inhibitors can join. They must have vaccinations against certain infections or take antibiotics if the vaccine was recent. People can't join if they've had certain treatments for aHUS, other kidney diseases, severe infections including COVID-19, or immune system disorders like lupus.

Inclusion Criteria

I have received all required vaccinations or will start antibiotics if my treatment begins sooner.

I have TMA, including low platelet count, blood cell destruction, and kidney issues.

Exclusion Criteria

I have liver disease or injury.

I have had a transplant involving bone marrow, heart, lung, small bowel, pancreas, or liver.

I have HUS due to drug exposure or specific genetic conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 200 mg oral doses of iptacopan twice daily for 26 weeks

26 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term safety and efficacy evaluations

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

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Iptacopan

Trial Overview The trial is testing Iptacopan's effectiveness and safety in treating aHUS in adults new to complement inhibitor therapy. It's a Phase 3 study which means it’s closer to potentially being approved for general use if successful.

How Is the Trial Designed?

Group I: Iptacopan 200 mg b.i.d Experimental Treatment 1 Intervention

Single arm open-label with 50 adult patients receiving 200mg oral twice daily doses of iptacopan

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

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]

In a study of six adult patients with hemolytic-uremic syndrome, the condition was linked to severe hypertension and renal damage, with three cases being idiopathic and two associated with oral contraceptive use.

The prognosis for adults with hemolytic-uremic syndrome is significantly worse than for children, as evidenced by the need for dialysis in three patients and one death due to complications like acute hemorrhagic pancreatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hemolytic-uremic syndrome in the adult (author's transl)]. Montoliu, J., Darnell, A., Torras, A., et al.[2006]

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]

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) has seen improved survival rates, now around 80%, due to advancements in plasma exchange treatments, shifting it from a previously fatal condition.

Recent registry data indicate that the prognosis of TTP/HUS varies significantly based on underlying mechanisms, clinical features, and whether the case is a primary or relapsed presentation, highlighting the syndrome's heterogeneity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TTP/HUS and prognosis: the syndrome and the disease(s). Forzley, BR., Clark, WF.[2019]

Iptacopan, a complement inhibitor, is being evaluated in a Phase 3 study (APPLAUSE-IgAN) involving approximately 450 adults with immunoglobulin A nephropathy (IgAN) to determine its efficacy in reducing proteinuria and slowing kidney function decline over 24 months.

The primary goal of the study is to show that iptacopan is superior to placebo in reducing the urine protein-to-creatinine ratio and in slowing the decline of estimated glomerular filtration rate, with safety and tolerability also being assessed as secondary outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. Rizk, DV., Rovin, BH., Zhang, H., 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]

Caplacizumab, a nanobody approved for treating acute episodes of acquired thrombotic thrombocytopenic purpura (aTTP), was shown to rapidly normalize platelet counts in 60 patients, with a median time of just 3 days.

The study suggests that caplacizumab can be effective even when treatment is initiated late and may allow for PEX-free regimens in some patients, indicating a potential shift in treatment protocols for aTTP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura. Völker, LA., Kaufeld, J., Miesbach, W., et al.[2022]

A treatment protocol for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) introduced at Johns Hopkins Hospital resulted in a 91% survival rate among 108 patients, demonstrating the efficacy of the treatment.

The combination of prednisone and plasma exchange was particularly effective for patients with severe symptoms, while prednisone alone was effective for those with milder cases, indicating a tailored approach to treatment based on symptom severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. Bell, WR., Braine, HG., Ness, PM., et al.[2022]

Pregnancy-associated atypical hemolytic uremic syndrome is a serious condition caused by uncontrolled activation of the complement system, leading to significant health risks.

Anti-C5 therapy is an effective treatment that can safely be stopped after the patient achieves complete remission, particularly in those with a low-risk genetic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing management. De Sousa Amorim, E., Blasco, M., Quintana, L., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04889430

NCT04889430 | Efficacy and Safety of Iptacopan (LNP023 ... The purpose of this Phase 3 study is to determine whether iptacopan (LNP023) is efficacious and safe for the treatment of aHUS in adult patients who are ...

2. novartis.com novartis.com/clinicaltrials/study/nct04889430

Efficacy and Safety of Iptacopan (LNP023) in Adult Patients ... Iptacopan (LNP023) is efficacious and safe for the treatment of aHUS in adult patients who are treatment naive to complement inhibitor therapy.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10334406/

Design and Rationale of the APPELHUS Phase 3 Open-Label ... APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS. Keywords: LNP023, aHUS, alternative pathway, atypical hemolytic uremic ...

4. journals.lww.com journals.lww.com/jasn/fulltext/2024/10001/iptacopan_in_c5_blockade_for_refractory_atypical.2807.aspx

Iptacopan in C5 Blockade for Refractory Atypical Hemolytic... Recent data on Iptacopan's use in C5 refractory Paroxysmal Nocturnal Hemoglobinuria provided a therapeutic rationale. An application for the compassionate use ...

5. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-effectiveness-and-safety-of-iptacopan-for-adults-with-atypical-hemolytic-uremic-syndrome-not-previously-treated-with-complement-inhibitors/

Study on the Effectiveness and Safety of Iptacopan ... This study investigates the safety and effectiveness of the drug iptacopan in treating adult patients with atypical hemolytic uremic ...

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

218276Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov Iptacopan did not impact the T cell-dependent antibody responses. Source: Reviewer's analysis. Abbreviations: aHUS, atypical hemolytic uremic syndrome; AP ...