A Safety Study of GSK3039294 in Healthy Volunteers and Patients With Systemic Amyloidosis
Condition: Amyloidosis
MeSH terms: Amyloidosis
Intervention: GSK3039294
Intervention description: GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK3039294; GSK2315698; systemic amyloidosis; CPHPC; dose-escalation

Summary:

      GSK3039294 has been developed in order to offer an orally available alternative to parenteral
      CPHPC (GSK2315698 [metabolite of GSK3039294]) for plasma serum amyloid P component (SAP)
      depletion prior to use of anti SAP monoclonal antibody (mAb) in the treatment of systemic
      amyloidosis. This phase 1 study is intended to study safety, tolerability and pharmacokinetic
      (PK) profile of GSK3039294 in humans. This study consists of three parts. Part A will
      evaluate safety and tolerability of single doses of GSK3039294 in healthy subjects, Part B
      will evaluate safety and tolerability of repeat doses of GSK3039294 in healthy subjects, and
      Part C will evaluate safety and tolerability of repeat doses of GSK3039294 in subjects with
      systemic amyloidosis. Part A is a single dose, open label, dose escalation study. Two cohorts
      of subjects will be enrolled to provide data from 6 subjects per cohort and up to 4 different
      doses (2 dose levels per cohort) of GSK3039294 will be tested. For Cohorts 1 and 2, each
      subject may take part in two dosing periods. Part B is repeat dose, open label, dose
      escalation study. Sufficient number of subjects will be enrolled in Cohort 3a to ensure 6
      completers (Cohort 3b will be conducted if required) and GSK3039294 will be administered
      repeatedly for a total of 21 days. Each subject will take part in a single study period. In
      Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in 12
      subjects with systemic amyloidosis. Each subject will take part in a single study period. The
      total duration for Part A is approximately 8 weeks, Part B is approximately 8-9 weeks, and
      Part C is approximately 13 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: 18 to 70 years of age inclusive at the time of signing the informed consent.

          -  Non-smokers and Smokers. Smokers (<5 /day) are permitted but must be willing to
             abstain for the duration of residential study sessions and / or dosing period
             (whichever is longer).

          -  Body weight >50 kilograms (kg) and body mass index (BMI) within the range 18.5-32
             kg/square meter (m^2) (inclusive) and excluding the effects of peripheral oedema.

          -  Male or female

          -  Female subjects are eligible to participate if they are of non-childbearing potential
             defined as premenopausal females with a documented tubal ligation or hysterectomy or
             bilateral oophorectomy; or postmenopausal defined as 12 month of spontaneous
             amenorrhea (in questionable cases a blood sample with simultaneous follicle
             stimulating hormone (FSH) >40 milli-international units (MIU)/milliliter (mL) and
             estradiol < 40 picograms (pg)/mL (147 picomoles [pmol]/liter [L]) is confirmatory

          -  Male subjects with female partners of child bearing potential must comply with one of
             the following contraception requirements from the time of first dose of study
             medication until completion of the follow-up visit: (a.) Vasectomy with documentation
             of azoospermia; (b.) Male condom plus partner use of one of the following
             contraceptive options: Contraceptive subdermal implant that meets the effectiveness
             criteria of a <1% rate of failure per year, as stated in the product label,
             Intrauterine device or intrauterine system that meets the standard operating procedure
             (SOP) effectiveness criteria including a <1% rate of failure per year, as stated in
             the product label, Oral Contraceptive either combined or progestogen alone, Injectable
             progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches, Occlusive
             cap (female diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel,
             cream or suppository). These allowed methods of contraception are only effective when
             used consistently, correctly and in accordance with the product label. The
             investigator is responsible for ensuring that subjects understand how to properly use
             these methods of contraception.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in the protocol.

          -  Additional Inclusion Criteria - Healthy Volunteers: Healthy as determined by a
             responsible and experienced physician, based on a medical evaluation including medical
             history, physical examination, laboratory tests and cardiac monitoring.

          -  Additional Inclusion Criteria - Healthy Volunteers: A subject with a clinical
             abnormality or laboratory parameter(s) which is/are not specifically listed in the
             inclusion or exclusion criteria, outside the reference range for the population being
             studied may be included only if the investigator in consultation with the Medical
             Monitor if required agree and document that the finding is unlikely to introduce
             additional risk factors and will not interfere with the study procedures.

          -  Additional Inclusion Criteria - Healthy Volunteers: aspartate aminotransferase (AST),
             alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5 upper limit of
             normal (ULN) (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated
             and direct bilirubin <35%)

          -  Additional Inclusion Criteria - Patients: Subject medically diagnosed with systemic
             amyloidosis

          -  Additional Inclusion Criteria - Patients: serum amyloid P component (SAP) scan
             identifying amyloid at any anatomical site, including subset of patients with
             moderate-large amyloid load in the liver

          -  Additional Inclusion Criteria - Patients: Up to and including New York Heart
             Association (NYHA) class 2 with a stable clinical cardiac status 12 weeks prior to
             screening

          -  Additional Inclusion Criteria - Patients: For Amyloid Light-chain (AL) amyloidosis
             patients, >=12 months post-chemotherapy with a stable free light chain (FLC) ratio in
             the preceding 4 months

          -  Additional Inclusion Criteria - Patients: estimated glomerular filtration rate (eGFR)
             >50 mL/minute

          -  Additional Inclusion Criteria - Patients: Alanine amino transferase (ALT) <=3x upper
             limit of normal (ULN) and bilirubin <=1.5x ULN (isolated bilirubin >1.5 xULN is
             acceptable if bilirubin was fractionated and direct bilirubin <35%), irrespective of
             alkaline phosphatase (ALP) level

          -  Additional Inclusion Criteria - Patients: Subject is ambulant and capable of attending
             the clinical unit

        Exclusion Criteria:

          -  Prohibited medication

          -  History of regular alcohol consumption within 6 months of the study defined as: For
             United Kingdom (UK )sites - healthy volunteers: an average weekly intake of >21 units
             for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol:
             a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL)
             measure of spirits.

          -  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

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.

          -  A positive pre-study drug/alcohol screen

          -  A positive test for human immunodeficiency virus (HIV) antibody

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 84 days

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer). Prior to Part A for subjects
             participating in Parts A and B

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day Lactating females

          -  Poor or unsuitable venous access

          -  Additional Exclusion Criteria - Healthy Volunteer: Current or chronic history of liver
             disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones)

          -  Additional Exclusion Criteria - Healthy Volunteer: corrected QT interval using
             Fridericia's formula (QTcF) >450 milliseconds (msec) from a mean of triplicate
             readings triplicate readings taken 5 minutes apart

          -  Additional Exclusion Criteria - Patients: Subject with mean QTcF of >480 msec from a
             mean of triplicate readings

          -  Additional Exclusion Criteria - Patients: First degree heart block deemed to require
             pacing; Second degree atrioventricular (AV) block Mobitz Type II; Trifasicular block;
             Ventricular tachyarrthymias - with the exception of bundle branch block, atrial
             fibrillation & first degree heart block not requiring pacing, or second degree AV
             block Mobitz Type I

          -  Additional Exclusion Criteria - Patients: 24 hour proteinuria >=5 g

          -  Additional Exclusion Criteria - Patients: A syncopal episode, of any causation, within
             4 weeks of screening

          -  Additional Exclusion Criteria - Patients: Average systolic blood pressure (SBP) <=90
             millimeter of mercury (mmHg) at Screening from triplicate readings

          -  Additional Exclusion Criteria - Patients: Implantable cardiac defibrillator (ICD)

          -  Additional Exclusion Criteria - Patients: Evidence of severe cardiac dysfunction
             within 12 months of screening, as diagnosed by a cardiologist, using Echocardiography
             or cardiac magnetic resonance imaging (MRI) i.e. markedly impaired ejection fraction
             (EF) (EF < 50% for cardiac amyloidosis patients), or cardiac imaging parameters of
             severe diastolic dysfunction (grade 3 or 4)

          -  Additional Exclusion Criteria - Patients: Anaemia hemoglobin <9 g/deciliter (dL)

          -  Additional Exclusion Criteria - Patients: Uncontrolled hypertension in a known
             hypertensive patient, or fulfilling diagnostic criteria of essential hypertension at
             screening

          -  Additional Exclusion Criteria - Patients: Presence of any co-morbid condition (e.g.
             severe or unstable coronary artery disease; moderate to severe chronic obstructive
             pulmonary disease) which in the opinion of the investigator would increase the
             potential risk to the subject

          -  Additional Exclusion Criteria - Patients: Non-amyloidosis causes of chronic liver
             disease (with the exception of Gilbert's syndrome or clinically asymptomatic
             gallstones)

          -  Additional Exclusion Criteria - Patients: Diabetes Mellitus

          -  Additional Exclusion Criteria - Patients: Glycosuria at Screening

          -  Additional Exclusion Criteria - Patients: Urine power of Hydrogen (pH) <6.0 at
             screening

          -  Additional Exclusion Criteria - Patients: Hypoalbuminemia (<30 nanomoles [nmol]/L)

          -  Additional Exclusion Criteria - Patients: Hypophosphatemia (less than 0.8 millimoles
             [mmol]/L)

          -  Additional Exclusion Criteria - Patients: Prothombin time >1.5xULN

          -  Additional Exclusion Criteria - Patients: Malabsorption syndrome of any aetiology

          -  Additional Exclusion Criteria - Patients: Compassionate use of CPHPC (GSK2315698) or
             participation in a separate clinical trial involving CPHPC within 3 months of
             screening

          -  Additional Exclusion Criteria - Patients: Currently taking any of the following
             esterase-cleaved prodrug medications: cerebyx, aquavan, spectracef, hepsera, viread

          -  Additional Exclusion Criteria - Patients: Anticoagulation therapy within 4 weeks of
             Screening

          -  Additional Exclusion Criteria - Patients: Currently receiving or have received within
             12 weeks of screening immunosuppressive anti-cytokine monoclonal antibodies (e.g.
             anti-tumor necrosis factor [anti-TNF] or anti-interleukin 1[anti-IL-1]), disease
             modifying drugs (e.g. methotrexate, gold or cyclophosphamide), or high-dose infusional
             steroids (e.g. methylprednisolone), with the exception of low-dose maintenance oral
             corticosteroids (e.g. <=30 milligrams (mg) prednisolone per day)