Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment (APPLY-PNH)

A Randomized, Multicenter, Active-comparator Controlled, Open-label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily LNP023 in Adult Patients With PNH and Residual Anemia, Despite Treatment With an Intravenous Anti-C5 Antibody.

This study was a multi-center, randomized, open-label, active comparator-controlled, parallel group study.

The purpose of this Phase 3 study in PNH patients presenting with residual anemia despite treatment with anti-C5 antibody, was to determine whether iptacopan is efficacious and safe for the treatment of PNH through demonstration of superiority of iptacopan compared to anti-C5 antibody treatment.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Intervention / Treatment: Drug: LNP023; Drug: Eculizumab; Drug: Ravulizumab

Detailed Description

The study comprised three periods:

• A screening period lasting up to 8 weeks (unless there was a need to extend it for vaccinations required for inclusion, vaccinations were started as early as possible to avoid extension of the screening period)
• A 24-week randomized, open-label, active controlled, treatment period for the primary efficacy and safety analyses. Patients who met the eligibility criteria at screening were stratified based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based on the transfusion history as reported during the last 6 months prior to randomization (i.e. transfusion received/not received). Patients were randomized to one of the two treatment groups in an 8:5 ratio to either iptacopan monotherapy at a dose of 200 mg orally b.i.d. or i.v. anti-C5 antibody treatment (patients continued with the same regimen during the randomized treatment period as they were prior to randomization), respectively.
• A 24-week open-label, iptacopan treatment extension period. The patients randomized to the active comparator group were offered to switch to iptacopan on Day 168 (Week 24 visit) and entered the treatment extension period, after receiving a last dose of anti-C5 antibody treatment (eculizumab or ravulizumab). For patients in the comparator group not agreeing to switch treatment, Week 24 visit was the End of Study visit for the trial with no participation in the treatment extension period. For patients agreeing to switch to oral iptacopan, the Extension treatment started on the day after completion of the Week 24 visit. The patients in the iptacopan group who, in the opinion of investigator, benefitted from treatment and were taking iptacopan at Week 24 visit (i.e. did not permanently discontinue study medication), were offered the opportunity to continue oral iptacopan treatment during the treatment extension period.
• Data cut-off date used for the primary results submission was 26- Sep-2022

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Santo Andre, SP, Brazil, 09090-790
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 01323-900
      • Novartis Investigative Site
• Czechia
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• France
  • Lille, France, 59037
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Riesa, Germany, 01589
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • AP
    • Ascoli Piceno, AP, Italy, 63100
      • Novartis Investigative Site
  • AV
    • Avellino, AV, Italy, 83100
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50139
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
  • VI
    • Bassano Del Grappa, VI, Italy, 36061
      • Novartis Investigative Site
• Japan
  • Kyoto, Japan, 606 8507
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 453-8511
      • Novartis Investigative Site
  • Fukushima
    • Fukushima city, Fukushima, Japan, 960 1295
      • Novartis Investigative Site
  • Ishikawa
    • Kanazawa-city, Ishikawa, Japan, 920-8641
      • Novartis Investigative Site
  • Nagano
    • Suwa, Nagano, Japan, 392-8510
      • Novartis Investigative Site
  • Osaka
    • Suita, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Novartis Investigative Site
• Netherlands
  • Nijmegen, Netherlands, 6500 MB
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
  • Galicia
    • Santiago De Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
  • Pais Vasco
    • San Sebastian, Pais Vasco, Spain, 20080
      • Novartis Investigative Site
• Taiwan
  • Hualien, Taiwan, 970
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
• United States
  • California
    • Duarte, California, United States, 91010
      • City Of Hope National Med Center City of Hope Medical Center
    • Orange, California, United States, 92868
      • Univ Cali Irvine ALS Neuromuscular
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University Georgia Patient Treatment
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Insitute Carolinas Healthcare System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation Dept.ofTaussigCancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by high-sensitivity flow cytometry with clone size ≥ 10%
• Stable regimen of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization
• Mean hemoglobin level <10 g/dL
• Vaccination against Neisseria meningitidis infection is required prior to the start of treatment.
• If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given

Exclusion Criteria:

• Participants on a stable eculizumab dose but with a dosing interval of 11 days or less or patients on stable ravulizumab dose but with a dosing interval of less than 8 weeks.
• Known or suspected hereditary complement deficiency at screening
• History of hematopoietic stem cell transplantation
• Patients with laboratory evidence of bone marrow failure (reticulocytes <100x10E9/L; platelets <30x10E9/L; neutrophils <500x10E6/L).
• Active systemic bacterial, viral (incl. COVID-19), or fungal infection within 14 days prior to study drug administration
• A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus.
• Major concurrent comorbidities including but not limited to severe kidney disease (e.g., eGFR < 30 mL/min/1.73 m2, dialysis), advanced cardiac disease (e.g., NYHA class IV), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), or hepatic disease (e.g., active hepatitis) that in the opinion of the investigator precludes participant's participation in the study.

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 200mg b.i.d.; Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d.	Drug: LNP023; Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral; Other Names: iptacopan
Active Comparator: Anti-C5 antibody; In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.	Drug: Eculizumab; Administered as intravenous infusion every 2 weeks as per the stable regimen, the maintenance dose is a fixed dose. Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion; Drug: Ravulizumab; Administered as intravenous infusion every 8 weeks, the maintenance dose is based on body weight. Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Marginal Proportion (Expressed as Percentages) of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 2 g/dL in the Absence of Red Blood Cell Transfusions	Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels ≥ 2 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.	Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Marginal Proportion (Expressed as Percentages) of Participants With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions	Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements taken at the visits occurring in last six weeks (between Day 126 and 168) of the randomized treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.	Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168
Percentage of Patients Meeting Hematological Response Criterion After the Start of LNP023 Treatment	Patients with hematological response are those with ≥ 2g/dL increase in hemoglobin from baseline regardless of transfusions and patients with Hb ≥ 12g/dL regardless of transfusions. Patients in the LNP023-LNP023 group received iptacopan from Day 1 to Day 336 (48 weeks) while patients in the anti-C5 antibody-LNP023 group received iptacopan from Day 169 to Day 336 (treatment extension period - 24 weeks).	Up to 48 weeks
Number of Patients Not Requiring RBC Transfusions After the Start of LNP023 Treatment	Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).	Up to 48 weeks
Change From Baseline in Hemoglobin at Visit Day 336	Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).	Baseline, Day 336
Change From Baseline in FACIT-Fatigue Questionnaire at Day 336	The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best. Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).	Baseline, Day 336
Adjusted Annualized Clinical BTH Rate After the Start of LNP023 Treatment	This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.	Up to 336 Days
Adjusted Annualized Major Adverse Vascular Events Rate After the Start of LNP023 Treatment	This endpoint is considering clinical BTH events after the start of LNP023 treatment. Therefore, results are presented in a single arm on LNP023 since it includes all patients in the Combined Full analysis set. Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.	Up to 336 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions	Marginal proportion (expressed as percentages) of participants who did not require transfusions between Day 14 and Day 168. Requiring red blood cell transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. These values include adjustment for baseline covariates and missing data has also been taken into account.	Between Day 14 and Day 168
Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period	Change from baseline in absolute reticulocyte count as mean of visits between Day 126 and Day 168	Baseline and mean of visits between Day 126 and 168
Ratio to Baseline in Log-transformed LDH in the Randomized Treatment Period	Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline in each treatment estimated between Day 126 and Day 168.The log transformation used refers to the natural log (base of e).	Baseline and mean of visits between Day 126 and 168
Adjusted Annualized Clinical BTH Rate in the Randomized Treatment Period	Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events are from negative binomial model. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment. The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis.	Between Day 1 and Day 168
Adjusted Annualized Major Adverse Vascular Events Rate in the Randomized Treatment Period	Adjusted annualized Major Adverse Vascular Events (MAVEs incl. thrombosis) rate. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. A patient with multiple occurrences of an event under one treatment is counted only once for that treatment.	Between Day 1 and Day 168
Change From Baseline in Hemoglobin Between Day 126 and 168	Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168. For this analysis, in order to factor out the effect of transfusions, if a patient had a transfusion during the randomized treatment period, then the hemoglobin values 30 days following the transfusion were excluded and hemoglobin data were imputed.	Baseline and mean of visits between Day 126 and 168
Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period	The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best.	Baseline, mean of visits between Day 126 and Day 168

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Absolute Reticulocyte Count at Day 336	Change from baseline in absolute reticulocyte count at visit Day 336. Patients randomized to anti-C5 antibody were switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).	Baseline and Day 336
Ratio to Baseline in Log-transformed LDH at Visit Day 336	Average of the Lactate dehydrogenase (LDH) log transformed ratio to baseline at visit Day 336.The log transformation used refers to the natural log (base of e). Patients randomized to anti-C5 treatment switched to LNP023 (iptacopan) on Day 169 and were treated until Day 336 (treatment extension period).	Baseline and Day 336

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2021
• Primary Completion (Actual): September 26, 2022
• Study Completion (Actual): March 6, 2023

Study Registration Dates

• First Submitted: August 27, 2020
• First Submitted That Met QC Criteria: September 16, 2020
• First Posted (Actual): September 22, 2020

Study Record Updates

• Last Update Posted (Estimated): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Anemia; Hemoglobin; Paroxysmal nocturnal hemoglobinuria; eculizumab; LNP023; ravulizumab
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Anemia; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab; Ravulizumab
• Other Study ID Numbers: CLNP023C12302; 2019-004665-40 (EudraCT Number)

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