Study to Evaluate the Efficacy and Safety of REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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The primary objective of the study is to demonstrate a reduction in intravascular hemolysis by REGN3918 over 26 weeks of treatment in patients with active PNH who are treatment-naive to complement inhibitor therapy or have not recently received complement inhibitor therapy. The secondary objectives of the study are: To evaluate the safety and tolerability of REGN3918. To evaluate the effect of REGN3918 on parameters of intravascular hemolysis To assess the concentrations of total REGN3918 in serum. To evaluate the incidence of treatment-emergent anti-drug antibodies to REGN3918 over time To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life

Official Title
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An Open-Label, Single Arm Study to Evaluate the Efficacy and Safety of REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Are Complement Inhibitor-Naive or Have Not Recently Received Complement Inhibitor Therapy

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: REGN3918


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) confirmed by high-sensitivity flow cytometry PNH granulocytes > 10% at screening visit Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms (eg, fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], history of a MAVE [including thrombosis], dysphagia, or erectile dysfunction) or history of red blood cell (RBC) transfusion due to PNH within 3 months of screening. Lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal (ULN) at screening visit. Key Exclusion Criteria: Prior treatment with a complement inhibitor either within 6 months prior to screening visit or at any time where the patient was refractory to complement inhibitor therapy, in the opinion of the investigator (with the exception of eculizumab refractory patients due to the C5 variant R885H/C) History of bone marrow transplantation Body weight < 40 kilograms at screening visit Peripheral blood absolute neutrophil count (ANC) <500/μL [<0.5 x 109/L] or peripheral blood platelet count <50,000/μL Documented history of systemic fungal disease or unresolved tuberculosis, or evidence of active or latent tuberculosis infection (LTBI) during screening period Any contraindication for receiving Neisseria meningitidis vaccination and antibiotic prophylaxis therapy as recommended in the study Any active, ongoing infection within 2 weeks of screening or during the screening period Any clinically significant abnormality identified at the time of screening that in the judgment of the Investigator or any sub-Investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases, or patients with short life expectancy Women who are pregnant, breastfeeding, or who have a positive pregnancy test at screening visit or day 1 NOTE: Other protocol defined Inclusion/Exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: REGN3918<br>Cohort A (Dose Confirmation) If a decision is made to expand Cohort A, patients will be assigned to Cohort A. Cohort B (Dose Expansion) If a decision is made to progress to Cohort B, patients will be assigned to Cohort B. | Drug: REGN3918<br>* Single intravenous (IV) dose, then a subcutaneous (SC) dose once weekly (QW).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Adequate Control of Intravascular Hemolysis | Participants were considered to have had adequate control of intravascular hemolysis if all of their lactose dehydrogenase (LDH) readings from Week 4 through Week 26 inclusive had values less than or equal to ≤ 1.5 × upper limit of normal (ULN). Participants must have greater than or equal to (≥) 50 percent (%) of scheduled LDH measures in those weeks, must not have had more than (>) 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. Participants were considered not to have had adequate control of intravascular hemolysis if they failed any of these criteria. | Week 4 through Week 26 | 
| Percentage of Participants Who Achieved Transfusion Avoidance | Transfusion avoidance was defined as not having received red blood cell (RBC) transfusion during the first 26 weeks. A transfusion was counted only if it was per-protocol, that is, it followed the predefined transfusion algorithm: RBC transfusion due to a post-baseline hemoglobin level < 9 grams per deciliter (g/dL) (with anemia symptoms) or a post-baseline hemoglobin level < 7 g/dL (without anemia symptoms). | Up to 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Had Breakthrough Hemolysis (BTH) | Breakthrough hemolysis was defined as the measurement of LDH ≥ 2 ULN concomitant with associated signs or symptoms at any time subsequent to an initial achievement of disease control (i.e., LDH ≤ 1.5 ULN). | Baseline up to 26 Weeks | 
| Percentage of Participants Who Achieved Normalization of Intravascular Hemolysis | A participant was considered to have achieved normalization of intravascular hemolysis if their LDH readings between Week 4 through Week 26 inclusive had values ≤ 1.0 ULN. A participant must have ≥ 50% of scheduled LDH measures in those weeks, must not have had > 2 consecutive visits without LDH measures, must not have experienced breakthrough hemolysis, and must not have discontinued study treatment early. A participant was considered not to have achieved normalization of intravascular hemolysis if they failed any of these criteria. | Week 4 through Week 26 | 
| Time to First Lactate Dehydrogenase (LDH) ≤1.5 x ULN | A time-to-first-event analysis was used to estimate the proportion of participants achieving transfusion avoidance at Week 26. | Up to Week 26 | 
| Percentage of Days With LDH ≤ 1.5 ULN From Week 4 Through Week 26 | Percentage of days was calculated as number of days with LDH ≤ 1.5 x ULN divided by the participant's total treatment duration (total number of days on treatment from Week 4 through Week 26). LDH ≤ 1.5 x ULN was used as an indicator of adequate control of intravascular hemolysis. | Week 4 through Week 26 | 
| Change From Baseline in LDH Levels at Week 26 | Change from baseline in LDH levels at Week 26 was reported. | Baseline, Week 26 | 
| Percent Change From Baseline in LDH Levels at Week 26 | Percent change from baseline in LDH levels at Week 26 was reported. | Baseline, Week 26 | 
| Rate of Transfusion With Red Blood Cells (RBCs) | The rate of transfusion with RBCs for a participant was the total number of transfusions divided by total person-years of time on treatment. | Baseline up to Week 26 | 
| Number of Units of Transfusion With RBCs | Transfusions with RBCs proceeded according to the following predefined criteria that triggered a transfusion; however, the actual number of units to be transfused is at the discretion of the investigator: • Transfuse with RBC(s) if the post-baseline hemoglobin level is <9 g/dL with symptoms resulting from anemia or • Transfuse with RBC(s) if the post-baseline hemoglobin level is <7 g/dL. | Baseline up to Week 26 | 
| Change From Baseline in RBC Hemoglobin Levels at Week 26 | Hemoglobin levels in participants with PNH was measured. Change from baseline in RBC hemoglobin at Week 26 was reported. | Baseline, Week 26 | 
| Change From Baseline in Free Hemoglobin Levels at Week 26 | Change from baseline in free hemoglobin levels at Week 26 was assessed. | Baseline, Week 26 | 
| Change From Baseline in Total Complement Hemolytic Activity Assay (CH50) at Week 26 | Change from baseline in total CH50 at Week 26 was reported. Here International units per milliliter was abbreviated as IU/mL. | Baseline, Week 26 | 
| Percent Change From Baseline in CH50 up to Week 26 | Percent change from baseline in CH50 up to Week 26 was reported. | Baseline up to Week 26 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 26 | The FACIT-F was a 13-item, self-reported PRO measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire was part of the FACIT measurement system, a compilation of questions measuring health-related QoL in participants with cancer and other chronic illnesses. The FACIT-fatigue assessed the level of fatigue using a 4-point Likert scale ranging from 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), 4 (very much) The sum of all responses resulted in the FACIT-F score for a total possible score of 0 to 52, with higher scores indicated greater fatigue. | Baseline, Week 26 | 
| Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) at Week 26 | The EORTC QLQ-C30 was a 30-item questionnaire used to assess symptoms and side effects of treatment and the impact on everyday life. It consists of 15 domains: 5 multi-item functioning scales (physical, role, social, emotional and cognitive), answered on a 4-point scale (1=Not at all,2=A Little,3=Quite a Bit,4=Very Much). Each score ranges from 0-100 with a higher score indicates higher level of functioning and a better QoL. A global health status/QoL scale that was answered on a 7-point scale (1=Very Poor to 7=Excellent). Each score ranges from 0-100 with a higher score indicates a better QoL. 9 symptom scales (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact), answered on a 4-point scale (1=Not at all, 2=A Little, 3=Quite a Bit, 4=Very Much). Each score ranges from 0 to 100 with a higher score indicates a higher level of symptoms, and a negative change from baseline indicates an improvement in symptoms. | Baseline, Week 26 | 
| Change From Baseline in European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Index Score | EQ-5D-3L was a self-administered standardized instrument for use as measure of health outcome. It comprised 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension rated on 3 levels scale: 1 (no problems), 2 (some problems), 3 (extreme problems). The summed score ranges from 5-15 with 5 corresponding to no problems and 15 to severe problems in 5 dimensions. EQ-5D index calculated by applying preference-based weights (tariffs) to scores of five health state dimensions. Index values range from -1 to 1, with 0 representing a health state equivalent to death and 1 representing perfect health. Total index EQ-5D-3L summary score was weighted with a range of -0.594 (worst) to 1.0 (best). | Baseline, Week 26 | 
| Change From Baseline in EQ-5D-3L Visual Analogue Scale (VAS) at Week 26 | The EQ-5D-3L was a standardized instrument for use as a measure of health outcome and was administered to all participants to assess the effect of the treatment on the participants' quality of life. The EQ-5D-3L includes a visual analog scale (VAS) which is a vertical scale with numbers ranging from 0 to 100. Participants were asked to draw a line to the place on the scale that best represented how good or bad his health was on that day. The worst state a participant can imagine was marked zero, and the best state the participant can imagine was marked 100. Mean change in VAS score from baseline was reported. | Baseline, Week 26 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs was defined as AEs that developed or worsened during the on-treatment period. SAE was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial/prolonged in-participant hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect/considered as medically important event. TEAEs included both Serious TEAEs and non-serious TEAEs. | Baseline up to Week 26 | 
| Number of Participants With TEAEs Based on Severity | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Severity of AEs was graded according to the following scale, Mild: event that does not generally interfere with usual activities of daily living; Moderate: event that interferes with usual activities of daily living, causing discomfort, permanent risk of harm; Severe: AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention. | Baseline up to Week 26 | 
| Number of Participants With Clinically Meaningful Changes in Clinical Laboratory Parameters | Clinical laboratory parameters included biochemistry, hematology and urinalysis. Number of participants with potential clinically significant changes in laboratory parameters which were deemed clinically meaningful by the investigator were reported. | Baseline up to Week 26 | 
| Number of Participants With Clinically Meaningful Changes in Vital Signs | Vital sign assessments included pulse rate, blood pressure (systolic and diastolic blood pressure) and body temperature. Number of participants with potential clinically meaningful changes in vital signs which were deemed clinically significant by the investigator were reported. | Baseline up to Week 26 | 
| Number of Participants With Clinically Meaningful Changes in 12-lead Electrocardiograms (ECGs) | 12-lead ECGs were evaluated. Any change in ECG assessments which are deemed clinically meaningful by the investigator were reported. | Baseline up to Week 26 | 
| Serum Concentrations of Total REGN3918 | Serum Concentrations of total REGN3918 was reported. | Pre-dose (Day 0), End of infusion at Days 0, 2, 7, 28, 56, 84, 112, 140, and 182 | 
| Number of Participants With Treatment-emergent Anti-Drug Antibodies (ADA) Response to REGN3918 | Number of Participants with treatment-emergent ADA response to REGN3918 was reported. | Baseline up to Week 26 |