Trial Outcomes & Findings for Study to Evaluate the Efficacy and Safety of REGN3918 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) (NCT NCT03946748)

During the study, the sponsor made an administrative decision to stop enrollment in order to pursue a combination program of REGN3918 \& cemdisiran for treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). Study was not stopped for any safety concerns or lack of efficacy. 28 participants were screened: 4 were screen failures (1-Lost to follow-up, 1-did not meet criteria, 1-other) \& 24 were enrolled \& treated. Enrollment was closed at 24 participants instead of 30-42 as planned in the protocol.

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

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.

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).

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).

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.

A time-to-first-event analysis was used to estimate the proportion of participants achieving transfusion avoidance at 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.

Change from baseline in LDH levels at Week 26 was reported.

Percent change from baseline in LDH levels at Week 26 was reported.

The rate of transfusion with RBCs for a participant was the total number of transfusions divided by total person-years of time on treatment.

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.

Hemoglobin levels in participants with PNH was measured. Change from baseline in RBC hemoglobin at Week 26 was reported.

Change from baseline in free hemoglobin levels at Week 26 was assessed.

Change from baseline in total CH50 at Week 26 was reported. Here "International units per milliliter" was abbreviated as "IU/mL".

Percent change from baseline in CH50 up to Week 26 was reported.

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.

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.

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).

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.

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.

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.

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.

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.

12-lead ECGs were evaluated. Any change in ECG assessments which are deemed clinically meaningful by the investigator were reported.

Serum Concentrations of total REGN3918 was reported.

Number of Participants with treatment-emergent ADA response to REGN3918 was reported.