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

Phase 2

Completed

Conditions: Paroxysmal Nocturnal Hemoglobinuria

Interventions: Biological: LFG316
Drug: LNP023

Registration Number: NCT02534909

Lead Sponsor: Novartis Pharmaceuticals

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).

Detailed Description: The study consisted of a 60-day screening period to assess eligibility and conduct vaccinations if required (for all patients not previously vaccinated at least 2 weeks prior to first dosing or if prior vaccination cannot be confirmed) and 4 treatment periods as follows. During the treatment period 1 (Days 1 to 29), all patients received infusions of LFG316 every 14 days. Following assessment of efficacy (hemolytic activity by serum LDH) at the end of treatment period 1, patients entered the optional 48-week treatment period 2 and continued LFG316 infusions every 14 days. At the end of treatment period 2, LFG316-responsive patients (assessed based on the investigator's judgment) were allowed to enter an additional extension period of up to 260 weeks (treatment period 3) in which they continued to receive LFG316 every 14 days. Period 4, which allowed patients to switch to LNP023, lasted approximately 21 weeks. During the first 4 weeks, patients continued to receive LFG316 in addition to oral administration of LNP023. After 4 weeks, patients discontinued LFG316 and continued with LNP023 monotherapy for approximately 16 weeks (+/- 28 days). Patients who participated in period 4 could join the long-term extension study CLNP023C12001B (NCT04747613) as soon as their eligibility was confirmed and study CLNP023C12001B was open to receive patients. There was no LNP023 treatment gap between the studies.

As per strategic decision, further development of LFG316 was terminated in favor of LNP023, Novartis offered patients enrolled in study CLFG316X2201 a conversion from LFG316 to LNP023, aiming to provide uninterrupted treatment for these PNH patients. The CLFG316X2201 trial was not a terminated study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LFG316 then LNP023	LFG316	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.
LFG316 then LNP023	LNP023	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Reduction in Serum Lactate Dehydrogenase (LDH) Levels Within the First 4 Weeks of LFG316 Treatment as Measured by Response Rate	Overall (Up to Week 4), Period 1 Day 8, Period 1 Day 15, Period 1 Day 22, Period 1 Day 29	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.
Percentage Change From Baseline in Serum Lactate Dehydrogenase (LDH) Levels Over the Entire Treatment Period	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)	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.

Secondary Outcome Measures

Name	Time	Method
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.	Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. AUC (0-tlast) was summarized using descriptive statistics.
Maximum Observed Serum Concentration (Cmax) for LFG316	Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.	Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Cmax was summarized using descriptive statistics.
Time to Reach Maximum Serum Concentration (Tmax) for LFG316	Pre-infusion and 2 hours after the end of infusion on Period 1 Day 1.	Venous whole blood samples were collected for activity-based pharmacokinetics characterization of LFG316. Pharmacokinetic parameters were determined using non-compartmental methods based on LFG316 concentrations in serum. Tmax was summarized using descriptive statistics. Actual sampling times were used for the calculation of PK parameters.
LFG316 Serum Concentration	Period 1 Day 1 (predose (trough), post-dose), Period 2 Day 337 (predose), Period 3 Day 1289 (predose)	The concentration of total LFG316 in serum was determined using Liquid chromatography/mass spectroscopy (LC/MS assay) and summarized using descriptive statistics.