Fasting blood glucose >126 mg/dL at screening. Heterozygous subjects will be excluded for a fasting blood glucose >140 mg/dL. 
Resting heart rate <45 bpm or >90 bpm at screening. 
Abnormal thyroid stimulating hormone (TSH) or thyroxine (T4) levels on screening. 
Elevated ALT or serum creatinine on screening or any clinically significant abnormalities on screening laboratory tests as determined by the Investigator. 
History of medically treated diabetes or of treated or medically diagnosed hypertension. Heterozygous subjects who have diagnosed hypertension and are well controlled on treatment (Refer to Exclusion Criteria 20 below), are eligible. . 
Presence of a skin lesion suspicious for malignancy, unless excised prior to Day 1. 
History of malignancy except for treated cervical carcinoma in situ in the past 5 years. 
Active or history of any clinically significant medical condition including renal, hepatic, pulmonary, gastrointestinal, cardiovascular, genitourinary, endocrine, immunologic, metabolic, neurologic, psychiatric or hematological disease, based on Investigator judgment. 
Acute illness or history of illness, which in the opinion of the Investigator, could pose a threat or harm to the subject or obscure interpretation of laboratory test results or interpretation of study data. 
Positive hepatitis B surface antigen, positive hepatitis C antibody or positive HIV test at screening or a history of positive testing (e.g. liver biopsy, serology) suggesting acute or chronic hepatitis. 
Abnormal 12-lead electrocardiogram (ECG) at screening or pre-dose (Day -1 or Day 1), except minor deviations deemed to be of no clinical significance by the Investigator. 
Received any experimental drugs or devices within 30 days or 5 half lives, whichever is longer, prior to dosing. 
Ongoing participation in a prior clinical study at the time of screening. 
Blood donation within 60 days prior to screening or intent to donate within 60 days after Final Study Visit. 
Hospitalization for major surgery including but not limited to abdominal, thoracic, or cardiovascular surgery within the past 3 months prior to screening, or for a clinically significant non-surgical illness, based on Investigator judgment, within the past 3 months. 
Planned elective surgery within 30 days of the Final Study Visit. 
Poor venous access or inability to tolerate venipuncture. 
History of significant drug hypersensitivity or anaphylaxis. 
History of hypersensitivity to proteins (e.g., allergy shots). 
Use of prescription medications on a regular basis. The last use of any prescription medication must have been greater than 5 half-lives for the specific medication or at least 14 days prior to admission (Day -1), whichever is longer. Hormonal contraception is allowed for female subjects. 
Heterozygous cohorts: Use of prescription medications on a regular basis is not allowed with the following exceptions: 
Antihypertensives (<3 medications on a stable dose for ≥ 30 days); 
Statins (dose must be ≤ half the maximum dose; must be on a stable dose ≥3 months); 
Fibrates (must be on stable dose for ≥3 months); 
Niacin (must be on stable dose for ≥3 months); 
Thyroxin (stable dose for ≥ 30 days); The last use of any other prescription medication will need follow the criteria for all other cohorts, as outlined above. 
Use of prescription medications not listed above may be allowed at the discretion of the Investigator upon consultation with Rhythm. 
Use of a non-prescription drug and herbal substances during the study (through the Final Study Visit). The last dose of any non-prescription drug must have been taken greater than 5 half-lives for that drug before receiving study drug. 
Inability to attend all study visits or to comply with protocol requirements including fasting and restrictions on alcohol, caffeine, nicotine and concomitant medication intake. 
A significant history of drug/solvent abuse within 5 years of screening or a positive test for drugs of abuse test at screening or on Day -1. 
Positive alcohol (breath test) or nicotine screen at Screening Visit or Day 1 (positive nicotine screen does not apply to heterozygous cohort). 
History of alcohol abuse (defined as average intake of three or more units of alcohol per day) within 5 years of the Screening Visit. 
History of tobacco or tobacco product use unless abstinent for at least one year prior to the Screening Visit. This criterion does not apply to heterozygous subjects. 
Previously randomized and dosed in this study. This criterion does not apply to heterozygous subjects. 
Any other reason, which in the opinion of the Investigator would confound proper evaluation of the study.       
    

NCT02431442_exc_T1
Measurement
Fasting blood glucose
NCT02431442_exc_T2
Value
>126 mg/dL
NCT02431442_exc_T3
Temporal
at screening
NCT02431442_exc_T4
Condition
Heterozygous
NCT02431442_exc_T5
Measurement
fasting blood glucose
NCT02431442_exc_T6
Value
>140 mg/dL
NCT02431442_exc_T7
Measurement
Resting heart rate
NCT02431442_exc_T8
Value
<45 bpm
NCT02431442_exc_T9
Value
>90 bpm
NCT02431442_exc_T10
Temporal
at screening
NCT02431442_exc_T11
Reference_point
screening
NCT02431442_exc_T12
Scope
<45 bpm or >90 bpm
NCT02431442_exc_T13
Measurement
thyroid stimulating hormone (TSH)
NCT02431442_exc_T14
Measurement
thyroxine (T4)
NCT02431442_exc_T15
Value
Abnormal
NCT02431442_exc_T16
Temporal
on screening
NCT02431442_exc_T17
Reference_point
screening
NCT02431442_exc_T18
Measurement
ALT
NCT02431442_exc_T19
Value
Elevated
NCT02431442_exc_T20
Measurement
serum creatinine
NCT02431442_exc_T21
Temporal
on screening
NCT02431442_exc_T22
Reference_point
screening
NCT02431442_exc_T23
Measurement
laboratory tests
NCT02431442_exc_T27
Value
abnormalities
NCT02431442_exc_T28
Condition
diabetes
NCT02431442_exc_T29
Qualifier
medically treated
NCT02431442_exc_T30
Drug
medically
NCT02431442_exc_T31
Procedure
medically treated
NCT02431442_exc_T32
Condition
hypertension
NCT02431442_exc_T33
Qualifier
treated
NCT02431442_exc_T34
Drug
medically
NCT02431442_exc_T35
Scope
treated or medically
NCT02431442_exc_T36
Observation
History
NCT02431442_exc_T37
Condition
Heterozygous
NCT02431442_exc_T39
Condition
hypertension
NCT02431442_exc_T40
Procedure
treatment
NCT02431442_exc_T41
Qualifier
well controlled
NCT02431442_exc_T44
Condition
skin lesion
NCT02431442_exc_T45
Qualifier
suspicious for malignancy
NCT02431442_exc_T46
Condition
malignancy
NCT02431442_exc_T47
Procedure
excised
NCT02431442_exc_T48
Temporal
prior to Day 1
NCT02431442_exc_T49
Reference_point
Day 1
NCT02431442_exc_T50
Condition
malignancy
NCT02431442_exc_T51
Observation
History
NCT02431442_exc_T52
Condition
cervical carcinoma in situ
NCT02431442_exc_T53
Qualifier
treated
NCT02431442_exc_T54
Procedure
treated
NCT02431442_exc_T55
Negation
except for
NCT02431442_exc_T56
Temporal
in the past 5 years
NCT02431442_exc_T57
Condition
medical condition
NCT02431442_exc_T58
Qualifier
clinically significant
NCT02431442_exc_T61
Observation
history
NCT02431442_exc_T62
Temporal
Active
NCT02431442_exc_T63
Scope
Active or history
NCT02431442_exc_T64
Condition
disease renal
NCT02431442_exc_T65
Condition
hematological disease
NCT02431442_exc_T66
Condition
psychiatric disease
NCT02431442_exc_T67
Condition
neurologic disease
NCT02431442_exc_T68
Condition
metabolic disease
NCT02431442_exc_T69
Condition
disease immunologic
NCT02431442_exc_T70
Condition
disease endocrine
NCT02431442_exc_T71
Condition
disease genitourinary
NCT02431442_exc_T72
Condition
disease cardiovascular
NCT02431442_exc_T73
Condition
disease gastrointestinal
NCT02431442_exc_T74
Condition
disease pulmonary
NCT02431442_exc_T75
Condition
disease hepatic
NCT02431442_exc_T76
Qualifier
based on Investigator judgment
NCT02431442_exc_T79
Scope
renal, hepatic, pulmonary, gastrointestinal, cardiovascular, genitourinary, endocrine, immunologic, metabolic, neurologic, psychiatric or hematological disease
NCT02431442_exc_T83
Measurement
hepatitis B surface antigen
NCT02431442_exc_T84
Value
Positive
NCT02431442_exc_T85
Measurement
hepatitis C antibody
NCT02431442_exc_T86
Value
positive
NCT02431442_exc_T87
Measurement
HIV test
NCT02431442_exc_T88
Value
positive
NCT02431442_exc_T89
Temporal
at screening
NCT02431442_exc_T90
Reference_point
screening
NCT02431442_exc_T91
Observation
history
NCT02431442_exc_T92
Scope
Positive hepatitis B surface antigen, positive hepatitis C antibody or positive HIV test
NCT02431442_exc_T93
Procedure
liver biopsy
NCT02431442_exc_T94
Procedure
serology
NCT02431442_exc_T95
Procedure
testing
NCT02431442_exc_T96
Value
positive
NCT02431442_exc_T97
Scope
liver biopsy, serology
NCT02431442_exc_T100
Condition
chronic hepatitis
NCT02431442_exc_T101
Condition
acute hepatitis
NCT02431442_exc_T102
Scope
acute or chronic hepatitis
NCT02431442_exc_T103
Procedure
12-lead electrocardiogram (ECG)
NCT02431442_exc_T104
Value
Abnormal
NCT02431442_exc_T105
Temporal
at screening
NCT02431442_exc_T106
Temporal
at pre-dose
NCT02431442_exc_T107
Reference_point
screening
NCT02431442_exc_T108
Reference_point
pre-dose
NCT02431442_exc_T109
Temporal
Day -1
NCT02431442_exc_T110
Temporal
Day 1
NCT02431442_exc_T111
Drug
experimental drugs
NCT02431442_exc_T112
Device
experimental devices
NCT02431442_exc_T113
Temporal
within 30 days
NCT02431442_exc_T114
Temporal
within 5 half lives
NCT02431442_exc_T115
Scope
experimental drugs or devices
NCT02431442_exc_T116
Scope
within 30 days or 5 half lives
NCT02431442_exc_T121
Procedure
Blood donation
NCT02431442_exc_T122
Temporal
within 60 days prior to screening
NCT02431442_exc_T123
Reference_point
screening
NCT02431442_exc_T124
Observation
intent to donate
NCT02431442_exc_T126
Temporal
within 60 days after Final Study Visit
NCT02431442_exc_T127
Reference_point
Final Study Visit
NCT02431442_exc_T128
Procedure
Hospitalization
NCT02431442_exc_T129
Procedure
surgery
NCT02431442_exc_T130
Qualifier
major
NCT02431442_exc_T133
Procedure
cardiovascular surgery
NCT02431442_exc_T134
Procedure
thoracic surgery
NCT02431442_exc_T135
Procedure
abdominal surgery
NCT02431442_exc_T136
Temporal
within the past 3 months prior to screening
NCT02431442_exc_T137
Reference_point
screening
NCT02431442_exc_T138
Condition
non-surgical illness
NCT02431442_exc_T139
Qualifier
clinically significant
NCT02431442_exc_T143
Temporal
within the past 3 months
NCT02431442_exc_T144
Scope
abdominal, thoracic, or cardiovascular surgery
NCT02431442_exc_T145
Procedure
elective surgery
NCT02431442_exc_T146
Observation
Planned
NCT02431442_exc_T148
Temporal
within 30 days of the Final Study Visit
NCT02431442_exc_T149
Reference_point
Final Study Visit
NCT02431442_exc_T150
Condition
Poor venous access
NCT02431442_exc_T151
Procedure
venipuncture
NCT02431442_exc_T152
Condition
inability to tolerate venipuncture
NCT02431442_exc_T153
Condition
drug hypersensitivity
NCT02431442_exc_T154
Condition
drug anaphylaxis
NCT02431442_exc_T155
Qualifier
significant
NCT02431442_exc_T157
Observation
History
NCT02431442_exc_T158
Condition
hypersensitivity to proteins
NCT02431442_exc_T159
Condition
hypersensitivity to allergy shots
NCT02431442_exc_T160
Drug
prescription medications
NCT02431442_exc_T161
Drug
any prescription medication
NCT02431442_exc_T162
Temporal
last use greater than 5 half-lives
NCT02431442_exc_T163
Temporal
at least 14 days prior to admission
NCT02431442_exc_T164
Reference_point
admission
NCT02431442_exc_T166
Temporal
regular basis
NCT02431442_exc_T167
Observation
History
NCT02431442_exc_T171
Drug
Antihypertensives
NCT02431442_exc_T172
Multiplier
<3 medications
NCT02431442_exc_T173
Qualifier
stable dose
NCT02431442_exc_T174
Temporal
for ≥ 30 days
NCT02431442_exc_T175
Drug
Statins
NCT02431442_exc_T176
Multiplier
≤ half the maximum dose
NCT02431442_exc_T177
Qualifier
stable dose
NCT02431442_exc_T178
Temporal
≥3 months
NCT02431442_exc_T179
Drug
Fibrates
NCT02431442_exc_T180
Qualifier
stable dose
NCT02431442_exc_T181
Temporal
≥3 months
NCT02431442_exc_T182
Drug
Niacin
NCT02431442_exc_T183
Qualifier
stable dose
NCT02431442_exc_T184
Temporal
≥3 months
NCT02431442_exc_T185
Drug
Thyroxin
NCT02431442_exc_T186
Qualifier
stable dose
NCT02431442_exc_T187
Temporal
≥ 30 days
NCT02431442_exc_T190
Drug
prescription medications
NCT02431442_exc_T191
Drug
non-prescription drug
NCT02431442_exc_T193
Drug
herbal substances
NCT02431442_exc_T194
Temporal
during the study
NCT02431442_exc_T196
Drug
any non-prescription drug
NCT02431442_exc_T165
Temporal
greater than 5 half-lives before receiving study drug
NCT02431442_exc_T199
Condition
drug/solvent abuse
NCT02431442_exc_T200
Observation
history
NCT02431442_exc_T201
Temporal
within 5 years of screening
NCT02431442_exc_T202
Reference_point
screening
NCT02431442_exc_T203
Measurement
drugs of abuse test
NCT02431442_exc_T204
Value
positive
NCT02431442_exc_T205
Temporal
at screening
NCT02431442_exc_T206
Reference_point
screening
NCT02431442_exc_T207
Measurement
breath test
NCT02431442_exc_T208
Measurement
alcohol test
NCT02431442_exc_T209
Scope
alcohol (breath test)
NCT02431442_exc_T210
Value
Positive
NCT02431442_exc_T211
Measurement
nicotine screen
NCT02431442_exc_T212
Temporal
at Screening Visit
NCT02431442_exc_T213
Reference_point
Screening Visit
NCT02431442_exc_T214
Scope
Positive alcohol (breath test) or nicotine screen
NCT02431442_exc_T215
Condition
alcohol abuse
NCT02431442_exc_T216
Observation
History
NCT02431442_exc_T217
Multiplier
three or more units per day
NCT02431442_exc_T218
Drug
alcohol
NCT02431442_exc_T219
Temporal
within 5 years of the Screening Visit
NCT02431442_exc_T220
Reference_point
the Screening Visit
NCT02431442_exc_T221
Observation
History
NCT02431442_exc_T222
Condition
tobacco use
NCT02431442_exc_T223
Condition
tobacco product use
NCT02431442_exc_T224
Condition
abstinent
NCT02431442_exc_T225
Temporal
for at least one year prior to the Screening Visit
NCT02431442_exc_T226
Reference_point
the Screening Visit
NCT02431442_exc_T227
Negation
unless
NCT02431442_exc_T228
Scope
tobacco or tobacco product use
NCT02431442_exc_T234
Procedure
Hormonal contraception
NCT02431442_exc_T235
Person
female