Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

A Multi-center, Randomized, Open-label, Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria and Active Hemolysis

This was a Phase II randomized, open-label, multicenter, efficacy, safety, pharmacokinetic and pharmacodynamic study assessing four iptacopan doses in adult Paroxysmal nocturnal hemoglobinuria (PNH) patients with active hemolysis who were not on eculizumab or any other complement inhibitor less than 3 months prior to first iptacopan dose. Active hemolysis was defined by a lactate dehydrogenase (LDH) value ≥ 1.5 × ULN.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: LNP023

Detailed Description

LNP023 is a novel oral small molecular weight compound, that inhibits alternative complement pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis.

The total study duration from Screening until end of study (EOS) was approximately 28 months. This three-period study included:

• Screening phase: of up to 8 weeks
• Period 1: a 4-week treatment period of iptacopan at the first dose in the assigned sequence
• Period 2: an 8-week treatment period at the second dose in the assigned sequence
• Period 3: an approximate 2-year treatment extension period for patients who responded to iptacopan treatment
• Taper down period of 2 weeks was applicable only for patients discontinuing iptacopan treatment (Week 13 for non-responders or Week 109 for responders who did not enter the rollover extension program (REP) (Study CLNP023C12001B / NCT04747613)). During this taper down period, patients were to receive 25 mg qd (once a day) of iptacopan for 7 days, followed by 10 mg qd for 7 additional days.
• An EOS visit that took place 1 week after the last iptacopan administration for patients not joining the REP. For patients joining the REP, the last treatment visit was the EOS visit.
• A safety follow-up call 30 days after the last administration of iptacopan was performed for patients not joining the REP.

Patients were randomized to Sequence 1 or Sequence 2 in a 1:1 ratio. Sequence 1: Four weeks of treatment with iptacopan 25 mg bid (Twice daily) in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 100 mg bid (starting from Study Day 17). If LDH was not reduced by ≥ 40% from the mean of pretreatment values at Week 4 (Day 29), the iptacopan dose was to be up-titrated to 200 mg bid in Period 2 and Period 3 (starting from Study Day 30). In the approximate 2-year treatment extension (Period 3), patients maintained the same treatment regimen as used in Period 2.

Sequence 2: Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 200 mg bid (starting from Study Day 17). In the approximate 2-year treatment extension (Extension Period 3), patients remained on 200 mg bid. No further up-titration was possible

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
• Malaysia
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88586
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients at least 18 years old at baseline.
3. Diagnosis of active PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by GPI-deficiency on flow cytometry (screening or medical history data acceptable).
4. LDH values > 1.5 x upper limit of the normal range (ULN) for at least 3 measurements over a maximum of 8 weeks prior to Day 1 (Screening, baseline or medical history data acceptable).
5. Hemoglobin level < 10.5 g/dL at Baseline.
6. For Period 3 of the study, patients who as per judgment of Investigator benefit from LNP023 treatment based on reduced hemolytic parameters as compared to Screening and Baseline.
7. Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae is required at least 4 weeks prior to first dosing with LNP023 (existing vaccinations should provide effective titers at time of LNP023 treatment start). If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
8. Able to communicate well with the investigator, to understand and comply with the requirements of the study. -

Exclusion Criteria:

1. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
2. Patients treated with eculizumab or any other complement inhibitor less than 3 months prior to study Day 1
3. Known or suspected hereditary or acquired complement deficiency.
4. History of currently active primary or secondary immunodeficiency.
5. History of splenectomy.
6. History of bone marrow/ hematopoietic stem cell or solid organ transplants (e.g. heart, lung, kidney, liver).
7. Evidence of malignant disease, or malignancies diagnosed within the previous 5 years.
8. Patients with laboratory evidence of bone marrow failure (reticulocytes < 60x10E9/L, or platelets < 50x10E9/L or neutrophils < 1x10E9/L) verified both at screening and baseline.
9. History of recurrent meningitis, history of meningococcal infections despite vaccination, as verified at both screening and baseline.
10. Presence or suspicion (based on judgment of the investigator) of active infection within 2 weeks prior to first dose of LNP023, or history of severe recurrent bacterial infections.
11. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening.
12. Patients on immunosuppressive agents such, as but not limited to, cyclosporine, tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate or IV immunoglobulins, less than 8 weeks prior to first treatment with LNP023, unless on a stable regimen for at least 3 months prior to first LNP023 dose.
13. Systemic corticosteroids unless on a stable dose for at least 4 weeks before randomization.
14. Severe concurrent co-morbidities not amenable to active treatment; e.g., patients with severe kidney disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), or unstable thrombotic event, as judged by the investigator, both at screening and baseline (unless baseline was skipped).
15. Any medical condition deemed likely to interfere with the patient's participation in the study, or likely to cause serious adverse events during the study.
16. History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
17. Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study.
18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LNP023 25 mg bid/100 mg bid; Four weeks of treatment with iptacopan 25 mg bid in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3.	Drug: LNP023; approximately 2 year of Treatment with LNP023; Other Names: iptacopan
Experimental: LNP023 50 mg bid/200 mg bid; Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3.	Drug: LNP023; approximately 2 year of Treatment with LNP023; Other Names: iptacopan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Lactate Dehydrogenase (LDH) Responders	A responder was defined as a patient with at least 60% reduction in LDH compared to Baseline or LDH below the upper limit of normal at any time up to and including Week 12 for that patient.	Week 2, week 4, week 8 and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in LDH Levels	LDH was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of Paroxysmal nocturnal hemoglobinuria (PNH)-associated hemolysis. Active hemolysis is defined by an LDH value ≥ 1.5x upper limit of normal (ULN) Baseline LDH was calculated as the average of the last three screening values prior to randomization. Serum was used to calculate the LDH values	Baseline, week 2, week 4, week 8 and week 12
Change From Baseline in Hemoglobin	Hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values.	Baseline, Week 2, week 4, week 8 and week 12
Change From Baseline in Free Hemoglobin	Free hemoglobin was used as a hemolysis marker to determine the dose-response effect of iptacopan on the reduction of PNH-associated hemolysis. Whole blood was used to calculate the hemoglobin values.	Baseline, Week 2, week 4, week 8 and week 12
Change From Baseline in Carboxyhemoglobin	Carboxyhemoglobin was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the carboxyhemoglobin values.	Baseline, Week 2, week 4, week 8 and week 12
Change From Baseline in Absolute Reticulocyte Count (ARC)	Reticulocyte count was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate the absolute reticulocyte count.	Baseline, week 2, week 4, week 8 and week 12
Red Blood Cell Count: Change From Baseline in Erythrocytes	Erythrocytes were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate erythrocytes values.	Baseline, week 2, week 4, week 8 and week 12
Change From Baseline in C3 Fragment Deposition on PNH RBC	C3 fragment deposition on paroxysmal nocturnal hemoglobinuria red blood cell (PNH RBC) was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Accumulation of C3 fragments on red blood cells make them prone to phagocytosis causing extravascular hemolysis. Whole blood was used to calculate C3 fragment deposition on PNH RBC values.	Baseline, week 2, week 4, week 8 and week 12
Mean Haptoglobin Levels	Haptoglobin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate haptoglobin levels.	Baseline, week 2, week 4, week 8 and week 12
Change From Baseline in Total Bilirubin	Bilirubin levels were used as a hemolysis marker to determine the effect of iptacopan on the reduction of PNH-associated hemolysis. Serum was used to calculate bilirubin levels.	Baseline, week 2, week 4, week 8 and week 12
Mean Platelets Count	Platelet counts were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate platelets count.	Baseline, week 2, week 4, week 8 and week 12
Mean Ferritin Levels	Ferritin levels were used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Serum was used to calculate ferritin levels.	Baseline, Week 4, Week 8 and week 12
Mean Clone Size	PNH clone size was used as a marker of intravascular and extravascular hemolysis to assess the effect of iptacopan. Whole blood was used to calculate clone size values.	Baseline, week 2, week 4, week 8 and week 12
Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax)	Cmax is the maximum (peak) observed plasma drug concentration after single dose administration (mass x volume-1). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.	Day 29 and 57
Pharmacokinetics Profile: Area Under the Curve Tau (AUCtau)	The AUCtau is the area under the plasma concentration-time curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1). AUCtau was estimated by imputing the 12-hour iptacopan plasma concentration as the PK profile's corresponding pre-dose (0-hour) value, that is, by assuming that at steady-state the iptacopan plasma concentration is the same as the beginning (pre-dose) and end (12 hours postdose) of the dosing interval. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.	Days 29 and 57
Pharmacokinetics Profile: Minimum Plasma Concentration (Cmin)	Cmin is the lowest plasma concentration observed during a dosing interval at steady state [mass / volume]. PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.	Days 29 and 57
Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax)	Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). PK parameters were determined, using non-compartmental method(s) with Phoenix WinNonlin (Version 8.3), from the plasma concentration-time data.	Days 29 and 57
Mean Fibrinogen Levels	Fibrinogen level was used as a marker associated with risk of thrombosis. Plasma was used to calculate fibrinogen levels.	Baseline, week 2, week 4, week 8 and week 12
Mean Prothrombin Time (PT)	Prothrombin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate prothrombin time.	Baseline, week 2, week 4, week 8 and week 12
Mean Activated Partial Thromboplastin Time (aPTT)	Activated partial thromboplastin time was used as a marker associated with risk of thrombosis. Plasma was used to calculate activated partial thromboplastin time.	Baseline, week 2, week 4, week 8 and week 12
Mean D-dimer Levels	D-dimer levels were used as a marker associated with risk of thrombosis. Plasma was used to calculate D-dimer levels.	Baseline, week 2, week 4, week 8 and week 12
Mean Thrombin Clotting Time	thrombin clotting time was used as a marker associated with risk of thrombosis. Plasma was used to calculate thrombin clotting time.	Baseline, Week 4, Week 8 and Week 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Jang JH, Wong L, Ko BS, Yoon SS, Li K, Baltcheva I, Nidamarthy PK, Chawla R, Junge G, Yap ES. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Adv. 2022 Aug 9;6(15):4450-4460. doi: 10.1182/bloodadvances.2022006960.

Helpful Links

• Patient Lay Trial Summary

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2019
• Primary Completion (Actual): April 7, 2020
• Study Completion (Actual): February 9, 2022

Study Registration Dates

• First Submitted: March 28, 2019
• First Submitted That Met QC Criteria: March 28, 2019
• First Posted (Actual): March 29, 2019

Study Record Updates

• Last Update Posted (Actual): June 18, 2024
• Last Update Submitted That Met QC Criteria: June 14, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: hemoglobin; Complement; PNH; hemolysis; LDH; paroxysmal nocturnal hemoglobinuria; Iptacopan; LNP023; alternative pathway
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: CLNP023X2204

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No