Proof of Concept Study to Assess the Efficacy, Safety and Pharmacokinetics of LFG316 in Patients With Paroxysmal Nocturnal Hemoglobinuria

NCT02534909 | Completed Phase 2 Results

• 2 other identifiers: CLFG316X22012014-005338-74
• Study Type: interventional
• Target: 10
• Locations: 3 countries
• Sites: 7

Brief Summary

The purpose of this study was to determine whether LFG316 can induce a hematological response, as measured by reduction in hemolytic activity, in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Conditions

Paroxysmal Nocturnal Hemoglobinuria

Keywords

Paroxysmal Nocturnal Hemoglobinuria (PNH); LFG316; LNP023

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate

  The primary efficacy variable for assessing the effect of LFG316 over the first 4 weeks of treatment was response rate where a patient was considered a responder if the percentage reduction from baseline in serum lactate dehydrogenase (LDH) was at least 60% at any time up to and including week 4 for that patient.

  Overall (Up to Week 4), Period 1 Day 8, Period 1 Day 15, Period 1 Day 22, Period 1 Day 29

• Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period

  Lactate dehydrogenase (LDH) levels were measured in serum samples and the percentage change from baseline was calculated. For serum LDH, baseline was the average of all pre-dose measurements.

  Baseline, Period 1 Day 29 (end of Treatment Period 1), Period 2 Day 365 (end of Treatment Period 2), Period 3 Day 1429 (end of Treatment Period 3), Period 4 Day 141 (end of Treatment Period 4)

Secondary Outcomes (4)

• Area Under the Concentration-time Curve (AUC) From Time Zero to the Last Measurable Serum Concentration Sampling Time (0-tlast) for LFG316

  Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.

• Maximum Observed Serum Concentration (Cmax) for LFG316

  Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.

• Time to Reach Maximum Serum Concentration (Tmax) for LFG316

  Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.

• LFG316 Serum Concentration

  Period 1 Day 1 (predose (trough), post-dose), Period 2 Day 337 (predose), Period 3 Day 1289 (predose)

Study Arms (1)

LFG316 then LNP023

EXPERIMENTAL

During treatment periods 1 to 3, the regimen included LFG316 at a dosage of 20 mg/kg administered as an intravenous (i.v.) infusion biweekly. In treatment period 4, the patients were given: * LFG316 at a dosage of 20 mg/kg as an i.v. infusion every two weeks for four weeks, amounting to two infusions in total. * LNP023 at a dose of 200 mg administered orally twice daily (b.i.d.) for approximately 20 weeks, with four 50 mg capsules taken at each administration.

Biological: LFG316; Drug: LNP023

Interventions

LFG316 BIOLOGICAL

LFG316 20 mg/kg was administered to all patients enrolled in the study: * Treatment Periods 1 to 3: LFG316 20 mg/kg as i.v. infusion every 2 weeks * Treatment Period 4: LFG316 20 mg/kg as i.v. infusion every 2 weeks for 4 weeks (total 2 infusions).

LFG316 then LNP023

LNP023 DRUG

Treatment Period 4: LNP023 200 mg b.i.d. for approximately 20 weeks. Four capsules (each 50 mg) were administered each time study medication was taken.

LFG316 then LNP023

Eligibility Criteria

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

You may qualify if:

• Written informed consent obtained before any assessment were performed.
• A documented PNH clone size of \>= 10% by RBCs and/or granulocytes, measured by GPI deficiency on flow cytometry.
• Serum LDH levels at least 1.5-fold above the ULN at screening.
• Patients receiving treatment with corticosteroids and/or other immunosuppressive regimens could continue treatment throughout the study, if indicated for treatment of autoimmune disease (e.g., aplastic anemia). It was strongly recommended, at the investigator's discretion, that patients receive appropriate prophylactic antibiotics (e.g., ciprofloxacin, penicillin, erythromycin) while on treatment with any type of concomitant immunosuppressive agent other than LFG316 (including corticosteroids).
• Negative pregnancy test for women of child-bearing potential at screening.
• Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 at least 2 weeks prior to first dosing, and vaccination against meningitidis type B if available and acceptable by local regulations, at least 2 weeks prior to first dosing.
• Able to communicate well with the investigator, to understand and comply with the requirements of the study.
• Patients included in this study after protocol amendment 6 were also to fulfill the following:
• To be carriers of the C5 gene minor variants as defined by nucleic acid changes that lead to amino acid exchanges in position p.Arg885.
• Patients who participated in period 3 of the current study who wanted to join the long-term extension study with LNP023 (CLNP023C12001B).
• Previous vaccination for the prevention of Streptococcus pneumoniae and Haemophilus influenzae at least 2 weeks prior to first dosing with LNP023 if locally available. If LNP023 treatment had to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment was required.

You may not qualify if:

• Known or suspected hereditary complement deficiency.
• History of hematopoietic stem cell transplantation.
• Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days or 5-times the half-life prior to screening. Note: clinical trials solely involving over-the-counter vitamins, off label use of drugs within published standard of care guidelines, supplements, or diet did not exclude an otherwise eligible patient.
• Female patients who were pregnant, breastfeeding, or intended to conceive during the course of the study.
• History of recurrent meningitis, history of meningococcal meningitis despite vaccination.
• Presence or suspicion (based on judgment of the investigator) of severe active bacterial infection within 2 weeks prior to first dose of LFG316, or severe recurrent bacterial infections.
• A positive HIV test result.
• Under active therapy with other agents interfering with the complement system (e.g., eculizumab) Wash-out time was at least 5 half-lives, approximately 8 weeks for eculizumab.
• Severe concurrent co-morbidities, e.g., patients with severe kidney disease (dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), unstable thrombotic event not amenable to active treatment as judged by the investigator.
• Either one of the following laboratory abnormalities at screening:
• Neutrophils \< 0.5 × 10\^9/L
• Platelets \< 30 × 10\^9/L
• Co-morbidities that were likely caused by underlying autoimmune diseases other than PNH, e.g., kidney disease in the context of lupus nephritis, ANCA-associated vasculitis.
• 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.
• History of hypersensitivity to a drug of the same class (human IgG1 monoclonal antibody) or any other excipient of the formulation.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (7)

Novartis Investigative Site

Brno-Bohunice, Czech Republic, 625 00, Czechia

Location

Novartis Investigative Site

Fukushima, Fukushima, 960 1295, Japan

Location

Novartis Investigative Site

Isehara, Kanagawa, 259-1193, Japan

Location

Novartis Investigative Site

Suita, Osaka, 565 0871, Japan

Location

Novartis Investigative Site

Shinjuku Ku, Tokyo, 160-0023, Japan

Location

Novartis Investigative Site

Niigata, 951 8520, Japan

Location

Novartis Investigative Site

Vilnius, LT-08661, Lithuania

Location

Related Links

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

MeSH Terms

Conditions

Hemoglobinuria, Paroxysmal

Condition Hierarchy (Ancestors)

Anemia, Hemolytic; Anemia; 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 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: All patients were on active treatment. In treatment periods 1 to 3, patients received the following: • LFG316 20 mg/kg as i.v. infusion every 2 weeks Patients participating in treatment period 4 received the following: * LFG316 20 mg/kg as i.v. infusion every 2 weeks for 4 weeks (total 2 infusions) * LNP023 200 mg b.i.d. for approximately 20 weeks. Four capsules (each 50 mg) were administered each time study medication was taken. Down-titration was permitted only in case of LNP023 treatment discontinuation: * LNP023 30 mg taken in the evening (once daily) for 7 days (3 capsules of 10 mg each time study medication was taken). * Followed by LNP023 10 mg taken in the evening (once daily) for 7 days (1 capsule of 10 mg each time study medication was taken). * LFG316 was administered via i.v. infusion by the investigator or designated study staff over approximately 2 hours in Period 1 and between 40 minutes and 2 hours from Period 2 onwards.

Study Record Dates

• First Submitted: August 7, 2015
• First Posted: August 28, 2015
• Study Start: September 9, 2015
• Primary Completion: May 24, 2022
• Study Completion: May 24, 2022
• Last Updated: May 16, 2025
• Results First Posted: November 1, 2024

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

JP (5); CZ (1); LI (1)