Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

NCT03439839 | Completed Phase 2 Results DMC

• 2 other identifiers: CLNP023X22012017-000888-33
• Study Type: interventional
• Target: 16
• Locations: 3 countries
• Sites: 3

Brief Summary

This was a Phase 2, open label, single arm, multiple dose study to assess efficacy, safety, pharmacokinetics and pharmacodynamics of iptacopan when administered in addition to Standard of care (SoC) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.

Conditions

Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis

Keywords

Complement; alternative pathway; paroxysmal nocturnal hemoglobinuria; hemolysis

Outcome Measures

Primary Outcomes (1)

• Percent Change From Baseline in Lactate Dehydrogenase (LDH) Level at Day 92

  Serum LDH was used as an intravascular hemolysis marker to assess the effect of iptacopan on the reduction of chronic hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) patients when administered in addition to SoC (monoclonal antibody with anti C5 activity) Baseline is defined as the mean of the last 3 measurements prior to dose administration.

  Baseline and Day 92

Secondary Outcomes (13)

• Absolute Change From Baseline in Lactate Dehydrogenase (LDH) Level

  Baseline, day 8, 15, 29, 57 and 92

• Absolute Change From Baseline in Hemoglobin

  Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

• Absolute Change From Baseline in Free Hemoglobin

  Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

• Absolute Change From Baseline in Reticulocytes Count

  Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

• Absolute Change From Baseline in C3 Fragment Deposition on PNH RBC

  Day 1 pre dose, day 8, 22, 29, 57, 92, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233

Study Arms (2)

Cohort 1: LNP023 200mg bid + SoC

EXPERIMENTAL

Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2

Drug: iptacopan; Combination Product: Standard of Care

Cohort 2: LNP023 50mg/200mg bid + SoC

EXPERIMENTAL

Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.

Drug: iptacopan; Combination Product: Standard of Care

Interventions

iptacopan DRUG

iptacopan bid orally administered

Also known as: LNP023

Cohort 1: LNP023 200mg bid + SoC; Cohort 2: LNP023 50mg/200mg bid + SoC

Standard of Care COMBINATION_PRODUCT

Standard of Care (SoC) is defined as an antibody with anti C5 activity. At the time of study start, eculizumab was the only available SoC; eculizumab will be hereafter referred to as SoC.

Cohort 1: LNP023 200mg bid + SoC; Cohort 2: LNP023 50mg/200mg bid + SoC

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients between the age of 18-80 (inclusive) at Baseline with a diagnosis of PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by glycosylphosphatidylinositol (GPI)-deficiency on flow cytometry (screening or medical history data acceptable).
• For Cohort 1 only: LDH values ≥1.5 × Upper limit of normal (ULN) range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (Screening, Baseline, or medical history data acceptable). All other Screening pre-SoC LDH values must be \>1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
• For Cohort 2 only: LDH values ≥1.25 × ULN range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (Screening, Baseline, or medical history data acceptable). All other Screening pre-SoC LDH values must be \>1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
• For Cohort 2 only: Hemoglobin level \<10.5 g/dL at Baseline.
• PNH patients on stable regimen of SoC complement blockade (monoclonal antibody with anti C5 activity) for at least 3 months prior to first treatment with iptacopan.
• Previous vaccination against N. meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with iptacopan. Vaccination against N. meningitidis type B should be conducted if available and acceptable by local regulations, at least 4 weeks prior to first dosing with iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
• Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.

You may not qualify if:

• Known or suspected hereditary complement deficiency at Screening.
• History of hematopoietic stem cell transplantation as verified both at Screening and at Baseline (unless baseline was skipped).
• Patients with laboratory evidence of bone marrow failure.
• A positive Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C test result at Screening.
• Presence or suspicion (based on judgment of the Investigator) of active infection within 2 weeks prior to first dose of iptacopan, or history of severe recurrent bacterial infections.
• History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at Screening and at Baseline (unless Baseline was skipped).
• Patients on immunosuppressive agents such as (but not limited to) cyclosporine, mycophenolate mofetil, tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with iptacopan unless on a stable regimen for at least 3 months prior to first iptacopan dose.
• Systemic corticosteroids administered at the dose of ≥10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with iptacopan.
• Severe concurrent co-morbidities; e.g., patients with severe kidney disease (dialysis), advanced cardiac disease (New York Heart disease Association (NYHA) class IV), severe pulmonary arterial hypertension (World Health Organization (WHO) class IV), unstable thrombotic event not amenable to active treatment as judged by the Investigator both at Screening and at Baseline (unless Baseline was skipped).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (3)

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Related Publications (1)

• Risitano AM, Roth A, Soret J, Frieri C, de Fontbrune FS, Marano L, Alashkar F, Benajiba L, Marotta S, Rozenberg I, Milojevic J, End P, Nidamarthy PK, Junge G, Peffault de Latour R. 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. Lancet Haematol. 2021 May;8(5):e344-e354. doi: 10.1016/S2352-3026(21)00028-4. Epub 2021 Mar 23.

  PMID: 33765419 RESULT

Related Links

• Patient Lay Trial Summary

MeSH Terms

Conditions

Hemoglobinuria, Paroxysmal; Hemolysis

Interventions

iptacopan; Standard of Care

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: No masking used in the study
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open label, non-randomized study

Study Record Dates

• First Submitted: February 14, 2018
• First Posted: February 20, 2018
• Study Start: April 9, 2018
• Primary Completion: April 22, 2020
• Study Completion: February 28, 2022
• Last Updated: June 12, 2024
• Results First Posted: January 3, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); FR (1); DE (1)