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

Eculizumab, approved for the treatment of PNH in many countries worldwide, is a
humanized monoclonal antibody directed against the terminal complement protein
C5. It blocks the formation of the MAC - C5b-9,thus protecting PNH RBCs from
complement-mediated intravascular hemolysis. The basis for approval of
eculizumab has been its effectiveness in PNH, as evidenced by the initial
reduction of lactate dehydrogenase (LDH) levels and by the long-term reduction
in the need for blood transfusions; decrease in the incidence of thrombosis;
improvement in anemia; and improvement in quality of life.
However, not all patients receive optimal therapeutic benefit. For example, 25%
of patients still need recurrent, albeit less frequent, blood transfusions. Up
to 20% of patients on eculizumab
therapy require significant increases in dose or dose frequency due to
breakthrough hemolysis secondary to incomplete inhibition of C5. In rare
instances, eculizumab is ineffective due to polymorphic variation in the gene
encoding C5 such that the protein is not recognized by eculizumab. The
heterogeneity in these hematological responses may be related to underlying
aplastic anemia, C3b-mediated extravascular hemolysis, or incomplete
pharmacologic blockade of C5, and rare polymorphisms in the gene coding for C5.
Eculizumab administration every 2
weeks (Q2W) by intravenous (IV) infusion has been described as burdensome for
patients.

REGN3918 is anticipated to provide better control of breakthrough hemolysis by
providing maximal and durable inhibition of C5 throughout the dosing interval,
improving the dosing
regimen, binding to the polymorphic variant C5 protein which renders eculizumab
ineffective, and development of a convenient subcutaneous formulation.

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.
- To evaluate the effect of REGN3918 on patient-reported outcomes (PROs)
measuring fatigue and health-related quality of life

This is an open-label, single arm, 26-week treatment study in patients with
confirmed diagnosis of PNH and active signs and symptoms who either are
complement inhibitor naïve or have received prior treatment with a complement
inhibitor, but not within 6 months prior to screening visit.

In this study, there will be two cohorts, one for dose confirmation (cohort A)
and one for dose expansion (cohort B). Dose confirmation will be made at the
interim analysis. The inclusion and exclusion criteria and schedule of events
are the same for cohort A and cohort B. During the assessment of data from
cohort A, recruitment into the study will continue, with patients recruited
being assigned subsequently as follows: if a decision is made to expand cohort
A, they will be assigned to cohort A. If a decision is made to progress to
cohort B, they will be assigned to cohort B.

Patients will be given a single loading dose of REGN3918 30 mg/kg intravenous
(IV) on day 1, then a dose not greater than 800 mg subcutaneous
(SC) once weekly (QW; ± 1 day) to week 26.

Patients will be given a single loading dose of REGN3918 30 mg/kg intravenous
(IV) on day 1, then a dose not greater than 800 mg subcutaneous
(SC) once weekly (QW; ± 1 day) to week 26.

-Additional visits to the hospital, additional physical tests, including a test
for gonnorhea and pregnancy.
-Possible rash or superficial irritation of the skin by the ECG stickers.
-In total about 600 ml blood will be taken, divided over 10 visits (Part A/B
and C). This amount won't cause any problems (to compare: a
blood donation involves 500ml of blood being taken each time). Possible side
effects of blood tests or biopsies are fainting,
contusions, sore spot and sensitive area at the injection site and, in rare
cases, an infection.