Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698
Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698
The study is intended to evaluate whether monthly repeated courses of administration of
 GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in
 patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and
 echocardiography (ECHO), and whether this is associated with an improvement in cardiac
 function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with
 immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post
 chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy.
 Primary objectives for the study are assessment of reduction in cardiac amyloid load after
 repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and
 assessment of safety & tolerability of repeated administration of Anti-SAP treatment,
 including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis.
 This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study
 in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis.
 Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a
 subject in the study is approximately 18 months.
Inclusion Criteria:

 -  Between 18 and 80 years of age inclusive, at the time of signing the informed consent.

 -  Male and female.

 Males:

 Male subjects with female partners of child bearing potential must comply with the
 following contraception requirements from the time of first dose of study medication for a
 cycle of spermatogenesis following five terminal half-lives after the last dose of study
 medication. Vasectomy with documentation of azoospermia.

 Male condom plus partner use of one of the contraceptive options below: Contraceptive
 subdermal implant, Intrauterine device or intrauterine system, Combined Oral Contraceptive
 or Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches .

 This is an all-inclusive list of those methods that meet the following GlaxoSmithKline
 (GSK) definition of highly effective: having a failure rate of less than 1% per year when
 used consistently and correctly and, when applicable, in accordance with the product label.
 For non-product methods (e.g., male sterility), the investigator determines what is
 consistent and correct use. The GSK definition is based on the definition provided by the
 International Conference on Harmonisation of Technical Requirements for Registration of
 Pharmaceuticals for Human Use (ICH).

 The investigator is responsible for ensuring that subjects understand how to properly use
 these methods of contraception.

 Females

 A female subject is eligible to participate if she is not pregnant (as confirmed by a
 negative Urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one
 of the following conditions applies:

 • Non-reproductive potential defined as: Pre-menopausal females with one of the following:
 Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with
 follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral
 Oophorectomy.

 Postmenopausal defined as: 60 years old; Twelve(12) months of spontaneous amenorrhea with
 an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of
 hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g.
 leuprolide treatment) in questionable cases a blood sample with simultaneous follicle
 stimulating hormone (FSH) and oestradiol levels consistent with menopause (refer to
 laboratory reference ranges for confirmatory levels). Females on HRT and whose menopausal
 status is in doubt will be required to use one of the highly effective contraception
 methods if they wish to continue their HRT during the study. Otherwise, they must
 discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

 • Reproductive potential and agrees to follow one of the options listed in the Modified
 List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
 Potential (FRP) (As mentioned in study protocol) from 30 days prior to the first dose of
 study medication and until 3 months after the last dose of study medication.

 The investigator is responsible for ensuring that subjects understand how to properly use
 these methods of contraception

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

 -  Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis

 -  LV mass on CMR > 200 grams (g) Inclusion Criteria for Group 1

 -  Transthyretin amyloid (ATTR) cardiomyopathy (CM)

 -  Subjects with a diagnosis of hereditary ATTR amyloidosis should have a known
 amyloidogenic transthyretin (TTR) mutation demonstrated by genotyping AND is
 recognised to be primarily associated with cardiomyopathy AND one of the following:
 Definite histochemical identification of amyloid by Congo red staining and green
 birefringence in crossed polarised light in cardiac or other tissue biopsy and
 identification of TTR as the amyloid fibril protein either by immunohistochemistry or
 proteomic analysis.

 Or Scintigraphy: 99m^Tc-DPD with Grade 2 cardiac uptake or 99m^Tc-PYP with either Grade 2
 or 3 cardiac uptake.

 -  Subjects with a diagnosis of wild type ATTR-CM must be negative by genotyping and have
 one of the following: Definite histochemical identification of amyloid by Congo red
 staining and green birefringence in crossed polarised light in cardiac or other tissue
 biopsy and identification of TTR as the amyloid fibril protein either by
 immunohistochemistry or proteomic analysis OR Scintigraphy
 99m^Technetium-dicarboxypropane diphosphonate (99m^Tc-DPD) with Grade 2 cardiac uptake
 or 99m^ Technetium-pyrophosphate (99m^Tc-PYP) with Grade 2 or 3 cardiac uptake.

 -  Clinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months
 preceding screening

 Inclusion Criteria for Group 2

 -  Subject medically diagnosed with AL amyloidosis that has required chemotherapy or an
 autologous stem cell transplant based upon:

 AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic
 identification of AL amyloid fibril type, in subjects with definite monoclonal gammopathy
 in whom causative mutations of all known relevant amyloidogenic genes have been excluded

 -  Clinically stable in NYHA class 2 or 3 for the 3 months preceding screening

 -  >=6 months after completing any line of chemotherapy, or after autologous stem cell
 transplantation, and having attained either a very good partial response (VGPR) or a
 complete response (CR), and without the need for haematological maintenance therapies

 Inclusion Criteria for Group 3

 -  Newly diagnosed AL amyloidosis based upon:

 AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic
 identification of AL amyloid fibril type in subjects with definite monoclonal gammopathy in
 whom causative mutations of all known relevant amyloidogenic genes have been excluded

 -  Mayo stage II or IIIa

 -  Confirmed free light chain complete response (CR) during the first three cycles of
 first-line chemotherapy where at least the first cycle has been with cyclophosphamide,
 bortezomib, dexamethasone (CyBorD).

 Exclusion Criteria:

 -  Cardiomyopathy primarily caused by non-amyloid diseases (e.g. ischemic heart disease;
 valvular heart disease)

 -  Interval from the Q wave on the ECG to point T using Fredericia's formula (QTcF) > 500
 millisecond (msec)

 -  Sustained / symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic
 VT, at screening

 -  Unstable heart failure defined as emergency hospitalization for worsening, or
 decompensated heart failure, or syncopal episode within 1 month of screening.

 Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at screening

 -  N-terminal pro b-type Natriuretic Peptide [(NT)-proBNP] >8500 nanograms (ng)/ Liter
 (L)

 -  Glomerular filtration rate (GFR) at Screening < 40 milliliter (mL)/minute (min)

 -  Any active and persistent dermatological condition

 -  Existing diagnosis of any type of dementia

 -  History of allogeneic stem cell transplantation, prior solid organ transplant, or
 anticipated to undergo solid organ transplantation, or left ventricular assist device
 (LVAD) implantation, during the course of the study.

 -  Malignancy within last 5 years, except for basal or squamous cell carcinoma of the
 skin, or carcinoma in situ of the cervix that has been successfully treated.

 -  Acute coronary syndrome, or any form of coronary revascularization procedure
 (including coronary artery bypass grafting [CABG]), within 6 months of screening.

 -  Stroke within 6 months of screening, or transient ischaemic attack (TIA) within 3
 months of screening

 -  Symptomatic, clinically significant autonomic neuropathy which the Principal
 Investigator (PI) feels will preclude administration of study treatment

 -  Hypoalbuminaemia (serum albumin < 30 g/L)

 -  Uncontrolled hypertension during screening

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

 -  Peripheral oedema at Screening that in the opinion of the Prinicpal Investigator (PI)
 or designee might prevent adequate absorption of subcutaneously administered CPHPC

 -  Urine dipstick positive (>1+) for blood during screening with investigation indicating
 glomerular haematuria. If other causes are identified, subjects may be enrolled on
 resolution of the abnormality

 -  Presence of any co-morbid or an uncontrolled medical condition (e.g. diabetes
 mellitus), which in the opinion of the investigator would increase the potential risk
 to the subject. Investigator should liaise with the Medical Monitor where there is
 uncertainty as to the eligibility of a patient

 -  Positive test for hepatitis B hepatitis C, and / or human immunodeficiency virus (HIV)
 during screening, or within 3 months prior to first dose of study treatment

 -  Unwillingness or inability to follow the procedures outlined in the protocol

 -  Use of GSK2315698 (CPHPC), or participation in a separate clinical trial involving
 CPHPC within 3 months of screening

 -  Any prohibited concomitant medication as per protocol within 28 days of Screening

 -  Donation of blood or blood products in excess of 500 mL within 84 days of screening

 -  Lactating females

 -  Poor or unsuitable venous access

 -  Treatment with another investigational drug, biological agent, or device within 6
 months of screening, or 5 half-lives of the study agent, whichever is longer.

 -  History of sensitivity to any of the study medications, or metabolite thereof or a
 history of drug or other allergy that, in the opinion of the investigator or Medical
 Monitor, contraindicates their participation CARDIAC MAGNETIC RESONANCE (CMR) SCANNING

 -  Orthopnoea of sufficient severity to preclude supine scanning as determined at
 screening

 -  Contraindication to magnetic resonance imaging (MRI) contrast agents

 -  Inability to fit inside scanner due to body size (girth)

 -  Contraindication for MRI scanning (as assessed by local MRI safety questionnaire),
 which includes but is not limited to:

 -  Intracranial aneurysm clips (except Sugita) or other metallic objects

 -  Intra- orbital metal fragments that have not been removed

 -  Pacemakers or other implanted cardiac rhythm management/monitoring devices and
 non-MR conditional heart valves

 -  Inner ear implants

 -  History of claustrophobia

 99m^TC-PYP OR 99mTC-DPD BONE TRACER RADIOSCINTOGRAPHY

 -  Orthopnoea of sufficient severity to preclude supine scanning as determined at
 Screening

 -  Previous allergic reaction to radioisotope bone tracers

 -  Previous inclusion in a research protocol involving nuclear medicine, positron
 emission tomography (PET) or radiological investigations with significant radiation
 burden (a significant radiation burden being defined as 10 mSv in addition to natural
 background radiation, in the previous 3 years).

 Exclusion Criteria for Group 1

 Has any of the following:

 -  Fulfilment of diagnostic criteria for AL amyloidosis

 -  TTR polyneuropathy and / or intracranial TTR involvement including ophthalmological
 disease

 -  Non-amyloidosis related chronic liver disease (with the exception of Gilbert's
 syndrome or clinically asymptomatic gallstones)

 -  Platelet count < 125x10^9 / L

 Exclusion criteria for Group 2

 -  Chronic liver disease or current active liver or biliary disease not attributable to
 amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 Exclusion criteria for Group 3

 -  Chronic liver disease or current active liver or biliary disease not attributable to
 amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 -  Platelet count < 75x10^9 /L