Basket Study to Assess Efficacy, Safety and PK of Iptacopan (LNP023) in Autoimmune Benign Hematological Disorders

Phase 2

Terminated

Conditions: Immune Thrombocytopenia (ITP)
Cold Agglutinin Disease (CAD)

Interventions: Drug: Iptacopan

Registration Number: NCT05086744

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease.

Detailed Description: This was an open-label, single-arm (within each cohort), multi-center, non-confirmatory basket study to assess the efficacy, safety and pharmacokinetics of iptacopan in participants with autoimmune benign hematological disorders. The study was set up as a basket study to allow inclusion of new cohorts (indications). The study included 2 cohorts: primary immune thrombocytopenia (ITP) and primary cold agglutinin disease (CAD). Participants in Cohort 1 (ITP) were stratified in two groups according to high/low complement activation (i.e., based on sC5b-9 level at screening). No additional cohorts were added during the study.

The study consisted of a screening period, a 12-week treatment period (Part A), a washout (for responders)/follow-up (for non-responders) period after Part A, and, for responders only, an additional treatment extension period for up to 24 months (Part B). Non-responders who had signs of clinical benefit according to the Investigator's assessment could also continue treatment with iptacopan in Part B. The washout period prior to the start of part B lasted up to 4 weeks.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 19

Inclusion Criteria

All Cohorts:

Written informed consent
Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections was required and vaccination against Haemophilus influenzae infection is recommended prior to the start of treatment.
Weight of at least 35 kg

Cohort 1 specific inclusion criteria:

Participants with a diagnosis of persistent or chronic primary ITP
Participants must have received at least 1 unique prior therapy administered with the intention to treat ITP
Sustained thrombocytopenia

Cohort 2 specific inclusion criteria:

Participants with a diagnosis of primary CAD
Participants must have received at least 1 unique prior therapy administered with the intention to treat CAD
Laboratory evidence of ongoing hemolysis
Sustained anemia

Exclusion Criteria

All cohorts:

Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations
Past or concomitant use of medications prohibited by the protocol
Known or suspected hereditary or acquired complement deficiency
History of primary or secondary immunodeficiency, including a positive HIV test result
Chronic infection with Hepatitis B or C virus
History of recurrent invasive infections caused by encapsulated organisms, including Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae
Presence or suspicion of any active infection within 14 days prior to first study drug administration.
Any medical condition deemed likely to interfere with the participant's participation in the study
Any malignant disease diagnosed within the past 5 years, with the exception of localized non-melanoma skin cancer, in situ cervical cancer, or, for CAD, a low-grade lymphoproliferative disorder.
History of bone marrow/hematopoietic stem cell or solid organ transplantation.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of investigational drug and for 1 week after last iptacopan dose
Active severe bleeding or history of intracranial hemorrhage.
Liver disease, or liver injury as indicated by abnormal liver function tests.
Severe concurrent comorbidities of unstable medical conditions.

Cohort 1 specific exclusion criteria:

Secondary ITP, as may arise in the setting of certain autoimmune disorders, immunodeficiency syndromes, infections, malignancies, and drug treatments
No ITP-directed background therapy permitted, with the exception of either a thrombopoietin receptor agonist or low-dose corticosteroid, as long as stable dosage for at least 4 weeks prior to first iptacopan dose
Abnormal coagulation screening labs

Cohort 2 specific exclusion criteria:

Secondary cold agglutinin syndrome, as may arise in the setting of certain infections, autoimmune disorders, and malignancies (with the exception of a low-grade lymphoproliferative disorder)
No CAD-directed background therapy permitted

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Iptacopan 200 mg BID	Iptacopan	Iptacopan 200 mg twice daily (BID) in participants with primary ITP and primary CAD

Primary Outcome Measures

Name	Time	Method
Cohort 1 (ITP): Number of Participants With a Clinically Meaningful Response	Up to 12 weeks (Part A)	A study participant with ITP was considered a responder if all the below criteria were met: 1. Platelet count of ≥50 k/μL sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat ITP 3. Lack of treatment discontinuation
Cohort 2 (CAD): Number of Participants With a Clinically Meaningful Response	Baseline, up to 12 weeks (Part A)	A study participant with CAD was considered a responder if all the below criteria were met: 1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 12-week treatment part 2. Absence of rescue therapy or prohibited medications to treat CAD 3. Lack of treatment discontinuation

Secondary Outcome Measures

Name	Time	Method
Cohort 1 (ITP): Time to First Platelet Count ≥50 k/μL	Up to 12 weeks (Part A)	The first time that a participant had a platelet count ≥50 k/μL after first dose of study treatment. Time to the first response was assessed for responders only.
Cohort 2 (CAD): Time to First Hemoglobin Level ≥1.5 g/dL Above Baseline	Baseline, up to 12 weeks (Part A)	The first time that a participant had a hemoglobin level ≥1.5 g/dL above baseline after first dose of study treatment. Time to the first response was assessed for responders only.
Cohort 1 (ITP): Duration of Time During Which Platelet Count Remains ≥50 k/μL Without the Use of Rescue Therapy	Up to 12 weeks (Part A)	The duration of response corresponds to the duration of time during which a participant's platelet count remains ≥50 k/μL without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
Cohort 2 (CAD): Duration of Time During Which Hemoglobin Level Remains ≥1.5 g/dL Above Baseline Without the Use of Rescue Therapy	Baseline, up to 12 weeks (Part A)	The duration of response corresponds to the duration of time during which a participant's hemoglobin level remained ≥1.5 g/dL above baseline without the use of rescue therapy. The duration of response was considered as cumulative if there were non-continuous periods of response. Duration of response was analyzed for responders only.
Cohort 1 (ITP): Magnitude of Platelet Count Increase From Baseline	Baseline, up to 12 weeks (Part A)	The magnitude of increase in platelet count compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: absolute platelet counts increase \<50, ≥50 and \<100, ≥100 and \<150, and ≥150 k/uL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
Cohort 2 (CAD): Magnitude of Hemoglobin Increase From Baseline	Baseline, up to 12 weeks (Part A)	The magnitude of increase in hemoglobin level compared to baseline was derived for each participant at each visit and time point. Best response across all visits is presented (highest value). The following categories were used: Hb increase from baseline by \<1, ≥1 and \<1.5, ≥1.5 and \<2, and ≥2 g/dL. This endpoint is only applicable to participants without rescue therapy in the treatment period.
Cohort 1 (ITP): Need for Rescue Therapy During Part A	Up to 12 weeks (Part A)	Rescue therapy was defined as any therapy with ITP indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For ITP, rescue therapy generally consisted of corticosteroids, intravenous immunoglobulins or anti-Rho(D) immunoglobulin and may had been indicated in case of worsening thrombocytopenia and/or signs or symptoms of bleeding.
Cohort 2 (CAD): Need for Rescue Therapy During Part A	Up to 12 weeks (Part A)	Rescue therapy was defined as any therapy with CAD indication that started on or after Day 1. Rescue therapy, if indicated, could be initiated at the Investigator's discretion. From Day 1 onwards, if rescue therapy was needed before response criteria were met, the participant was treated as a non-responder. Conversely, use of rescue therapy after the primary endpoint was met, would not impact the response status with respect to that endpoint. For CAD, rescue therapy generally consisted of plasmapheresis, intravenous immunoglobulins (IVIG) and/or red blood cell transfusions and may had been indicated in case of worsening anemia and/or critical hemolysis.
Cohort 2 (CAD): Change From Baseline in Lactate Dehydrogenase (LDH)	Baseline, up to 12 weeks (Part A)	LDH was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Cohort 2 (CAD): Change From Baseline in Total Bilirubin	Baseline, up to 12 weeks (Part A)	Total bilirubin was measured in serum samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Cohort 2 (CAD): Change From Baseline in Reticulocyte Count	Baseline, up to 12 weeks (Part A)	Reticulocyte count was measured in blood samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Cohort 2 (CAD): Change From Baseline in Haptoglobin	Baseline, up to 12 weeks (Part A)	Haptoglobin was measured in serum or plasma samples to assess the effect of treatment with iptacopan on relevant disease biomarkers.
Cohort 1 and 2: Number of Participants With AEs and SAEs During the On-treatment Period in Part A and B	From first dose of study treatment to 7 days after last dose, up to approximately 43 weeks (Cohort 1) and 103 weeks (Cohort 2)	Number of participants with AEs (any adverse events regardless of seriousness) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For CTCAE v5.0, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. The on-treatment period is defined from the day of first administration of study drug up to 7 days after the last administration of study drug.
Cohort 1 and 2: Maximum Observed Plasma Concentration (Cmax) of Iptacopan	Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A	Pharmacokinetic (PK) parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Cohort 1 and 2: Time to Maximum Observed Plasma Concentration (Tmax) of Iptacopan	Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A	PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) observed concentration following a dose. Actual sampling times were considered for the calculation of PK parameters.
Cohort 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Iptacopan	Pre-dose, 0.5, 2, 4 and 6 hours after iptacopan administration on Day 15 and Day 57 of Part A	PK parameters were calculated based on iptacopan plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve (AUC) calculation.
Cohort 1 and 2: Trough Plasma Concentration (Ctrough) of Iptacopan	Pre-dose on Day 15, 29 and 57 of Part A	Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.