A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis
A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis
The study will be conducted in two parts. The first (Part A) will be an open label single
 dose escalation part beginning with the proposed starting dose level of GSK2398852 as 5
 milligram (mg) [approximately equivalent to 0.1 mg/kilogram (kg)]. The next escalation dose
 levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg. GSK2315698 will be
 administered at variable doses until the concentration of the serum amyloid P component
 monoclonal antibody (SAP mAb) has fallen below 100 nanogram/millilitre (ng/mL). Decisions
 about these next dose levels will be made following safety review of the prior subjects'
 data; dose levels may be changed (increased and lowered) and dose levels may be repeated
 depending on the observed safety such that Part A extension study may be performed. In
 addition, pharmacokinetics of GSK2315698 (SAP depleter) and GSK2398852 (anti-SAP mAb), and
 circulating SAP concentrations will be assessed. Dose escalation in Part A will continue to
 the highest well tolerated dose or the highest allowable dose. Subjects will be closely
 monitored and will undergo Equilibrium contrast Magnetic Resonance Imaging (EqMRI) including
 organ volume, Elastography and Liver Biopsy if required.

 Part B will be a randomized partially blinded part with the principal objective of assessing
 the dose response of the GSK2398852 in more detail. Subjects will be assigned to one of
 approximately 5 dose groups from Part A. The precise selection of numbers of subjects and
 dose levels will be informed by the results from Part A.
Inclusion Criteria:

 -  Subject has been medically diagnosed with systemic amyloidosis and falls into one of
 the patient groups (small to moderate amyloid load involving the spleen for Part A;
 moderate to large amyloid load involving the spleen (to a moderate/large extent) for
 Part A (following agreement from external safety committee); moderate to large amyloid
 load involving the spleen and liver (spleen involved to a moderate/large extent) for
 Part A extension (if required); and moderate to large amyloid load involving the
 spleen (and liver in subset of subjects only) for Part B).

 -  Alanine aminotransferase (ALT) <3x upper limit of normal (ULN) and bilirubin <1.5x ULN
 (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct
 bilirubin <35%).

 -  Male or female between 18 and 70 years of age inclusive, at the time of signing the
 informed consent.

 -  Subject is ambulant and capable of attending for the study visit schedule.

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form.

 -  A female subject is eligible to participate if she is of non-childbearing potential;
 or females on hormone replacement therapy (HRT) and whose menopausal status is in
 doubt will be required to use one of the approved contraception methods.

 -  Male subjects with female partners of child-bearing potential must agree to use one of
 the approved contraception methods.

 -  Smokers (<10 /day) are permitted but must be willing to abstain for the duration of
 residential study sessions

 Exclusion Criteria:

 -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
 result within 3 months of screening

 -  The subject has participated in a clinical trial and has received an investigational
 therapeutic product (unlicensed) within the following time period prior to the first
 dosing day in the current study: 3 months, 5 half-lives or twice the duration of the
 biological effect of the investigational product (whichever is longer). This timeframe
 will not apply to short term administration of GSK2315698 in study CPH114527.

 -  Pregnant females as determined by positive serum or urine human chorionic gonadotropin
 (hCG) test at screening or prior to dosing.

 -  Lactating females.

 -  Estimated glomerular filtration rate (GFR)<30 milliliter (mL)/minute (min) [<60 mL/min
 for the first 4 subjects to be enrolled]

 -  Evidence of an active urinary sediment on microscopy as evidenced by the presence of
 red cell casts

 -  Decompensated cardiac failure or a recent history of syncope associated with cardiac
 disease.

 -  In a subject in whom there is a clinical suspicion of cardiac amyloid, an
 echocardiogram is consistent with significant cardiac amyloid, whether symptomatic or
 not.

 -  Clinically significant anaemia- hemoglobin (Hb) <9 gram (g)/deciliter (dL).

 -  Use of prohibited medications.

 -  Poor or unsuitable venous access.

 -  Subjects with a QT interval corrected using Fridericia's formulas (QTcF) of >480 ms or
 other electrocardiogram (ECG) abnormalities which, in the opinion of the investigator
 are clinically significant and may increase safety risk.

 -  Uncontrolled hypertension with systolic blood pressure (BP) >170 mmHg and /or
 diastolic >100 mmHg

 -  Presence of any co-morbid condition (e.g. severe or unstable coronary artery disease;
 moderate-severe chronic obstructive pulmonary disease) which in the opinion of the
 investigator would increase the potential risk to the subject.

 -  Subjects with active vasculitis

 -  Exclusions from Equilibrium contrast Magnetic Resonance Imaging (EqMRI) scanning
 [Contraindications to Magnetic Resonance Imaging (MRI) scanning including, but not
 limited to: Intracranial aneurism clips (except Sugita); History of intra-orbital
 metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray);
 Pacemakers and non-MR compatible heart valves; Inner ear implants; History of
 claustrophobia; estimated GFR <30 mL/min (gadolinium exclusion)]

 -  Subjects with dementia or a diagnosis of cerebral amyloid angiopathy.