A Multicenter single-arm Extension Study to Describe the Long-term Safety
of AMG 416 in the Treatment of Secondary Hyperparathyroidism in Subjects With
Chronic Kidney Disease on Hemodialysis.

SHPT is characterized by persistently elevated PTH levels and occurs commonly
among patients with CKD largely as an adaptive response to maintain mineral
homeostasis. Among patients managed with dialysis, SHPT is associated with
important disturbances in calcium and phosphorus metabolism including
hyperphosphatemia, pathological changes in bone described collectively as renal
osteodystrophy, soft-tissue and vascular calcification, left ventricular
hypertrophy, and cardiovascular events. The importance of managing SHPT is
highlighted by recommendations provided in clinical practice guidelines such as
the Kidney Disease Outcomes Quality Initiative (KDOQI) from the National Kidney
Foundation (NKF) and the Kidney Disease Improving Global Outcomes (KDIGO)
initiative (KDIGO, 2009; K/DOQI, 2003). The effect of AMG 416 to lower the
serum levels of iPTH, calcium, and phosphorus among subjects with SHPT
receiving hemodialysis was demonstrated initially in early phase clinical
trials that included a randomized, double-blind, placebo-controlled, single
ascending dose (SAD) study and a randomized, double-blind, placebo-controlled
multiple ascending dose (MAD) study. The efficacy and safety of AMG 416 in this
patient population was evaluated further in a phase 2, open-label, 12-week,
dose titration study and in a subsequent, ongoing 40-week open-label extension
study.
Additional information about the long-term safety and tolerability of AMG 416
in the management of SHPT among patients receiving hemodialysis would be
beneficial to the overall understanding of the AMG 416 program. The study is
descriptive and no formal hypothesis will be tested. The study will
characterize the ongoing management of SHPT among subjects receiving
hemodialysis and the ability of AMG 416 to maintain plasma iPTH levels within
the KDIGO recommended range in subjects previously treated with AMG 416.

Primary: characterize the long-term safety and tolerability of AMG 416 in the
treatment of secondary hyperparathyroidism (SHPT) in subjects with chronic
kidney disease (CKD) on hemodialysis.
Secondary: to characterize intact parathyroid hormone (iPTH), total serum
albumin corrected calcium (cCa), and serum phosphorous (P) values in the
treatment of SHPT in subjects with CKD who are on hemodialysis, who are being
treated with AMG 416.

This is a phase 3, interventional, open-label, single-arm extension study,
designed to assess the long-term safety and tolerability of AMG 416.
The overall study design is described by a study schema at the end of the
protocol synopsis section in the protocol. Also see section "aanvullende
informatie".

Subjects entering from open-label parent studies AMG 416 Study 20120231 or
20120334 will receive a starting dose of AMG 416 thrice weekly (TIW) with
intravenous (IV) administration after hemodialysis identical to the last dose
received in the parent study. Subjects entering from randomized, double-blind
parent Study 20120360, will receive a starting dose of 2.5 mg AMG 416 TIW
administered IV after hemodialysis. All subjects will continue to receive AMG
416 until approximately 2.5 years after the first subject enrolls. All subjects
will continue to receive background standard of care (other than cinacalcet) as
mandated by individual Investigator. See Section 6 of the protocol.
Procedures: For subjects from open-label parent studies: After providing
written informed consent, subjects from parent studies AMG 416 20120231 and
20120334 enter a screening period of up to 30 days which is concurrent with the
last 30 days of investigational product while
in the parent study. Subjects are enrolled into the current study without
immediately undergoing the 30-day washout period from the parent study. These
subjects will defer the 30-day washout of study drug from the parent study,
until the end of the current study. In the current study, subjects will
continue receiving AMG 416 at the same dose as in the parent study. This dose
may be 0 mg if investigational product was on suspension at the end of the
open-label parent study. Every effort must be made to ensure there is no
interruption in dosing between the end of the parent study and the start of the
current study. Subjects are defined as enrolled on the day of their next
hemodialysis session after receiving the last dose in the parent study,
contingent upon providing written informed consent and meeting all eligibility
criteria. For those subjects with recently suspended AMG 416 dosing however,
dosing with AMG 416 must not resume until all dose resumption criteria have
been met (see Sections 6.2.2.4 * 6.2.2.7 in the protocol).
For subjects from a double-blind parent study: After providing written informed
consent, subjects from AMG 416 parent Study 20120360 enter a screening period
of up to 30 days. The screening period in the current study should be
concurrent with the mandatory 30-day washout of investigational product at the
conclusion of treatment in Study 20120360, as described in the protocol for
Study 20120360. All subjects will start at a dose of 2.5 mg of AMG 416 upon
meeting all dosing conditions as described in Section 6.2.2.2 of the protocol.
For subjects from all parent studies: dose titration of AMG 416 is at the
discretion of the Investigator and will be based upon the values of the site*s
contracted laboratory provider iPTH and Ca (cCa, total Ca, or ionized Ca), with
the frequency of these laboratory draws at the discretion of each individual
Investigator, per standard of care for subjects receiving treatment with a
calcimimetic agent. At a minimum however, calcium and albumin must be measured
monthly. Doses of AMG 416 should in general be adjusted to maintain iPTH levels
above the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice
guidelines of 2x the ULN, but no greater than 9x the ULN, with the ULN based on
the reference range of the assay used at the individual site. Guidance for
titration of AMG 416 dose has been provided based on trends in iPTH within this
range. See Section 6.2.2.3 in the protocol.
Concomitant therapy with active vitamin D analogues, calcium supplements, and
phosphate binders may be adjusted as needed throughout the study, based on
Investigator clinical judgment. Dialysate calcium concentration may be adjusted
as needed throughout the study, but must be maintained * 2.25 mEq/L. The site*s
contracted provider for standard of care laboratory values for subjects
receiving treatment with a calcimimetic agent will be used to determine AMG 416
dose titration throughout the study. Additional blood samples must be obtained
for pregnancy testing for women of childbearing potential (WOCBP) and for
antidrug antibodies (ADA). Subjects will be followed for safety throughout the
treatment period, and for 30 days after the last dose of AMG 416.
The treatment period will continue for approximately 2.5 years after the first
subject enrolls in the study. Dosing of AMG 416 is to be directed by the
Investigator, using his/her best medical judgment. Dosing with AMG 416 may be
modified or suspended, based on protocol guidance for the predialysis
contracted provider laboratory iPTH or Ca (cCa, total Ca, or ionized Ca)
symptomatic hypocalcemia, or other drug-related advers events.
For a full list of study procedures, including the timing of each procedure,
please refer to Section 7 and the Schedule of Assessments (Table 3) in the
protocol.

A treatment regimen for SHPT that includes standard of care and AMG 416 will
increase the proportion of subjects who will have a reduction in iPTH. SHPT is
characterized by persistently elevated PTH levels and occurs commonly among
patients with CKD largely as an adaptive response to maintain mineral
homeostasis. Among patients managed with dialysis, SHPT is associated with
important disturbances in calcium and phosphorus metabolism including
hyperphosphatemia, pathological changes in bone described collectively as renal
osteodystrophy, soft-tissue and vascular calcification, left ventricular
hypertrophy, and cardiovascular events.

Four clinical studies have been completed to date. Most adverse events (AE)
were mild or moderate in severity. The incidence of nausea, vomiting and
diarrhea were similar in the AMG 416- and placebo-treated subjects. Serious
adverse events (SAEs) have been reported; none were considered related to study
drug. Administration of foreign proteins poses a small risk of developing
antibody-mediated hypersensitivity reactions, including anaphylaxis. Such
reactions are often related to release of cytokines or vasoactive amines.
Symptoms may include fever, chills, rigor/shakes, hypotension, respiratory
distress, rash/urticaria, and arthralgias and myalgias. However, AMG 416 is a
small peptide produced by chemical synthesis that is unlikely to be
immunogenic. The overall clinical safety findings to date suggest that AMG 416
is well-tolerated. Furthermore, the burden for the patient is relatively low as
they do not have to have extra visits during the treatment phase. AMG 416
provides the opportunity for hemodialysis patients with SHPT to increase
compliance over an oral calcimimetic and have one less oral regimen to manage
as AMG 416 is dosed 3 times a week, concurrent with hemodialysis and
administered by the dialysis site staff. For patients the long term safety of
AMG 416 is important information.