A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis

This is an interventional treatment trial for Amyloidosis focused on measuring pharmacokinetic, systemic amyloidosis, safety, dose escalation, Carboxy Pyrrolidine Hexanoyl Pyrrolidine Carboxylate (CPHPC), biomarker, GSK2315698, GSK2398852, SAP, pharmacodynamic, co-administration, intravenous Read More

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.