Iptacopan for Atypical Hemolytic Uremic Syndrome

(APPELHUS Trial)

Recruiting at85 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Novartis Pharmaceuticals

Must not be taking: Complement inhibitors

Disqualifiers: ADAMTS13 deficiency, Transplantation, Sepsis, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing iptacopan, a new medication, in adults with a rare disease called aHUS. The drug aims to calm an overactive part of their immune system to improve their health.

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.

What data supports the effectiveness of the drug Iptacopan for atypical hemolytic uremic syndrome?

The research does not provide direct evidence for Iptacopan's effectiveness in atypical hemolytic uremic syndrome, but it mentions that similar conditions involving complement system dysregulation, like pregnancy-associated atypical hemolytic uremic syndrome, can be effectively treated with anti-C5 therapy, which controls complement activation. ^{1 2 3 4 5}

How is the drug Iptacopan unique in treating atypical hemolytic uremic syndrome?

Iptacopan is unique because it is an oral medication that specifically targets and inhibits factor B in the alternative complement pathway, offering a convenient alternative to current treatments that require intravenous administration and carry a higher risk of infection. ^{6 7 8 9 10}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Iptacopan (Complement Inhibitor)

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.

Participant Groups

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

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

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]

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]

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 (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 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]

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]

References

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

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura. [2022]

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

Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Eculizumab in pregnancy-associated atypical hemolytic uremic syndrome: insights for optimizing management. [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

[Hemolytic-uremic syndrome in the adult (author's transl)]. [2006]

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

TTP/HUS and prognosis: the syndrome and the disease(s). [2019]

6. 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]

7. 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]

8. 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]

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

Targeting the Alternative Complement Pathway With Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE-IgAN Study. [2023]

10. 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]