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

NCT04558918 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CLNP023C123022019-004665-40
• Study Type: interventional
• Target: 97
• Locations: 12 countries
• Sites: 39

Brief Summary

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.

Conditions

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Keywords

Paroxysmal nocturnal hemoglobinuria; Hemoglobin; Anemia; LNP023; eculizumab; ravulizumab

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (7)

• Marginal Proportion (Expressed as Percentages) of Participants Who Remain Free From Transfusions

  Between Day 14 and Day 168

• Change From Baseline in Hemoglobin Between Day 126 and 168

  Baseline and mean of visits between Day 126 and 168

• Change From Baseline in FACIT-Fatigue Questionnaire in the Randomized Treatment Period

  Baseline, mean of visits between Day 126 and Day 168

• Change From Baseline in Absolute Reticulocyte Count in the Randomized Treatment Period

  Baseline and mean of visits between Day 126 and 168

• Ratio to Baseline in Log-transformed LDH in the Randomized Treatment Period

  Baseline and mean of visits between Day 126 and 168

Other Outcomes (2)

• Change From Baseline in Absolute Reticulocyte Count at Day 336

  Baseline and Day 336

• Ratio to Baseline in Log-transformed LDH at Visit Day 336

  Baseline and Day 336

Study Arms (2)

LNP023 200mg b.i.d.

EXPERIMENTAL

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

Anti-C5 antibody

ACTIVE COMPARATOR

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; Drug: Ravulizumab

Interventions

LNP023 DRUG

Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral

Also known as: iptacopan

LNP023 200mg b.i.d.

Eculizumab DRUG

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

Anti-C5 antibody

Ravulizumab DRUG

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

Anti-C5 antibody

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (39)

City Of Hope National Med Center City of Hope Medical Center

Duarte, California, 91010, United States

Location

Univ Cali Irvine ALS Neuromuscular

Orange, California, 92868, United States

Location

Augusta University Georgia Patient Treatment

Augusta, Georgia, 30912, United States

Location

Levine Cancer Insitute Carolinas Healthcare System

Charlotte, North Carolina, 28204, United States

Location

Cleveland Clinic Foundation Dept.ofTaussigCancer Center

Cleveland, Ohio, 44195, United States

Location

Novartis Investigative Site

Santo André, São Paulo, 09090-790, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 01323-900, Brazil

Location

Novartis Investigative Site

Ostrava, Poruba, 708 52, Czechia

Location

Novartis Investigative Site

Lille, 59037, France

Location

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Toulouse, 31059, France

Location

Novartis Investigative Site

Aachen, 52074, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Hamburg, 20246, Germany

Location

Novartis Investigative Site

Riesa, 01589, Germany

Location

Novartis Investigative Site

Ulm, 89081, Germany

Location

Novartis Investigative Site

Ascoli Piceno, AP, 63100, Italy

Location

Novartis Investigative Site

Avellino, AV, 83100, Italy

Location

Novartis Investigative Site

Florence, FI, 50139, Italy

Location

Novartis Investigative Site

Milan, MI, 20122, Italy

Location

Novartis Investigative Site

Roma, RM, 00161, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Bassano del Grappa, VI, 36061, Italy

Location

Novartis Investigative Site

Nagoya, Aichi-ken, 453-8511, Japan

Location

Novartis Investigative Site

Fukushima, Fukushima, 960 1295, Japan

Location

Novartis Investigative Site

Kanazawa, Ishikawa-ken, 920-8641, Japan

Location

Novartis Investigative Site

Suwa, Nagano, 392-8510, Japan

Location

Novartis Investigative Site

Suita, Osaka, 565 0871, Japan

Location

Novartis Investigative Site

Shinjuku-ku, Tokyo, 160-0023, Japan

Location

Novartis Investigative Site

Kyoto, 606 8507, Japan

Location

Novartis Investigative Site

Nijmegen, 6500 MB, Netherlands

Location

Novartis Investigative Site

Seoul, 06351, South Korea

Location

Novartis Investigative Site

Donostia / San Sebastian, Basque Country, 20080, Spain

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Santiago de Compostela, Galicia, 15706, Spain

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Novartis Investigative Site

Hualien City, 970, Taiwan

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Novartis Investigative Site

Leeds, LS9 7TF, United Kingdom

Location

Novartis Investigative Site

London, SE5 9RS, United Kingdom

Location

Related Publications (3)

• DeCastro C, Sheinberg P, Han B, Vallow S, Bermann G, Dhalke M, Kumar R, Dickie G, Galipeau N, Lamoureux R, Rupinski K, Lowe C, Nieves A, de Fontbrune FS, de Latour RP. Patient-Reported Meaningful Change in Symptoms and Impacts of Paroxysmal Nocturnal Hemoglobinuria (PNH) in Three Phase III Clinical Trials of Iptacopan. Patient. 2025 Nov;18(6):699-712. doi: 10.1007/s40271-025-00755-5. Epub 2025 Jul 22.

  PMID: 40694294 DERIVED

• Risitano AM, Kulasekararaj AG, Scheinberg P, Roth A, Han B, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Lee LWL, Yap ES, Frieri C, Marano L, de Fontbrune FS, Gandhi S, Trikha R, Alashkar F, Yang C, Liu H, Kelly RJ, Hochsmann B, Lawniczek T, Mahajan N, Solar-Yohay S, Kerloeguen C, Ferber P, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, de Latour RP. Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors. Lancet Haematol. 2025 Jun;12(6):e414-e430. doi: 10.1016/S2352-3026(25)00081-X.

  PMID: 40447351 DERIVED

• Peffault de Latour R, Roth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Hochsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. doi: 10.1056/NEJMoa2308695.

  PMID: 38477987 DERIVED

Related Links

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

MeSH Terms

Conditions

Hemoglobinuria, Paroxysmal; Anemia

Interventions

iptacopan; eculizumab; ravulizumab

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic Syndromes; Bone Marrow Diseases

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 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2020
• First Posted: September 22, 2020
• Study Start: January 25, 2021
• Primary Completion: September 26, 2022
• Study Completion: March 6, 2023
• Last Updated: October 9, 2024
• Results First Posted: November 28, 2023

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

US (5); CZ (1); IT (7); BR (2); FR (3); JP (7); DE (5); KR (1); NL (1); TW (2); ES (3); GB (2)