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Poster #: 1451
Clinical Pharmacokinetics of MicroRNA-122 Inhibitor RG-101 Administered as a Single Dose to
HCV and Non-HCV Infected End-Stage Renal Disease Patients Undergoing Hemodialysis
Compared to Normal Renal Function Subjects
Jacqueline
Paul
1
Grint ,
Therapeutics, San Diego, CA
Introduction and Background
Methods
AntimiRs are single-stranded synthetic oligonucleotides that sequester a target microRNA
(miR) in diseased cells to form an inactive heteroduplex. RG-101 is a GalNAc-conjugated antimiR-122 that inhibits the interaction of hepatitis C virus (HCV) with a host factor miR (miR-122)
needed to support viral replication (Figure 1). Inhibition of miR-122 results in significantly
reduced viral titers of HCV infected livers. GalNAc conjugation affords preferential targeting of
RG-101 to hepatocytes, by high affinity binding to highly expressed asialoglycoprotein
receptors on hepatocytes that are responsible for removal of target glycoproteins from the
systemic circulation. Once taken up into hepatocytes, RG-101 is metabolized to its active
unconjugated antimiR (RG1649). RG-101 is currently being evaluated as a potential treatment
option (in combination with direct acting antiviral agents) for HCV infected patients with or
without renal insufficiency. In previously conducted Phase 1 clinical testing (healthy male and
female subjects), single subcutaneous (SC) doses of RG-101 in the dose range of 0.5 to 8
mg/kg appeared to be safe and well tolerated. In addition, nonclinical findings suggested we
might see up to ~2- to 3-fold increases in RG-101 plasma exposure measures in human endstage renal disease (ESRD) patients receiving a 2 mg/kg dose. In this ‘reduced PK study’, we
compared the clinical pharmacokinetics of RG-101 in HCV and non-HCV infected subjects
with ESRD undergoing hemodialysis to subjects with normal renal function.
Table 1. Study Cohorts and Pharmacokinetic Sample Collection
6.2 (19.9%)
[4.7–8.8]
0.63 (30.2%)
[0.41–0.94]
8.2 (13.7%)
[6.9–10.6]
3.5
[2.0–5.0]
Single SC dose of RG-101
@ 2 mg/kg
ESRD Patients
(Cohort 2, N=8)
8.7 (52.7%)
[4.7–23.2]
1.14 (72.3%)
[0.41–3.48]
5.9 (28.9%)
[3.8–8.7]
3.0
[1.0–6.0]
ESRD + HCV Patients
(Cohort 3, N=8)
8.6 (53.0%)
[3.4–18.2]
1.22 (84.6%)
[0.37–3.09]
5.8 (27.0%)
[3.9–8.1]
2.6
[0.5–5.0]
*Cohorts 1 and 2 only were pair-wise matched in terms of gender, age, and weight (but not race) to potentially better facilitate PK
comparison
**All ESRD patients enrolled in Cohorts 2 and 3 were on hemodialysis and produced no urine for analysis
Note: Additional ‘post-48-hour’ plasma samples in the 24-week follow up period were also collected for analysis, but these results
are not yet available
• Results shown as geometric mean (%CV) [min–max], except for Tmax shown as median [min–max]
• RG-101 was only drug-related moiety seen in plasma at 0–48 hours postdose in all cohorts
• All tested urine samples from healthy subjects (Cohort 1) were BLOQ, indicating that <1% of the total administered dose was
eliminated in urine
Analytes
• RG-101 (conjugated parent
compound + other minor conjugated
moieties)
• RG1649 (main active unconjugated
metabolite + other minor
unconjugated moieties)
• TOTAL: RG-101 + RG1649
ESRD Patients
(Cohort 2; N=8)
ESRD + HCV Patients
(Cohort 3; N=8)
 Zepatier and Viekira Pak plus ribavirin: approved for
HCV/CKD GT1 and 4 without dose adjustments
 Estimated number of HCV-infected persons on dialysis
could reach ~60K by 2020
 IFN + RBV: 48 weeks treatment not ideal with low SVR rates
(Liu Ann Int Med 2013)
*Butt,
et al. HCV Infection and the Incidence of CKD. Am J Kidney Dis.
2011;57(3):396-402
 Sofosbuvir: controversial use in severe CKD due to
accumulation of metabolites (limited data, lack of controlled
trials)
Open label Phase 1 study assessing safety and PK of RG-101 in patients with ESRD
undergoing hemodialysis (HD) compared to healthy subjects with normal renal function (i.e.,
“worst case” comparison). Endpoints included PK, safety/tolerability, and effects on HCV RNA
(Cohort 3 only and findings not shown).
138.1
[96.1–198.4]
179.9
[108.2–299.1]
Table 2. Demographics & Baseline Characteristics
Mean Age (SD)
Male (n, [%])
Race
White (n, [%])
Black (n, [%])
Mean Weight (SD) (kg)
Creatinine (mg/dl)
Fibroscan Grade
Grade 0-1
Grade 2
Grade 3
Baseline Log10 HCV RNA (mean, [SD])
E S R D
192.8
[115.9–320.5]
Number (%) Subjects Reporting:
Any adverse event (AE)
2 (25.0%)
AEs by severity:
Mild
2 (25.0%)
Moderate
0
Severe**
0
Related to study drug
1 (12.5%)
AE leading to withdrawal
0
Serious AEs*
0
Fatal AEs
0
Results
Methods
Study Design and Endpoints
139.5
[97.1–200.4]
Cohort 1
Healthy
(N=8)
Unmet need in GT2, 3, 5, and 6 in HCV + CKD Population
 Prevalence of HCV infection in patients on dialysis
ranges from 6%–23%
100
H e a lth y S u b je c t
2 .0
E S R D + H C V
S A E
P a tie n t (E S R D + H C V )
1 .5
1 .0
0 .5
0 .0
H o u r
Table 5. Summary of Adverse Events
Key patient populations with HCV infection and chronic kidney disease (CKD) still remain
underserved for certain HCV genotypes:
High prevalence of HCV infection in patients
with ESRD*
100
2 .5
8
Healthy Subjects
(Cohort 1; N=8)
A ll C o h o r ts v s . S A E P a tie n t
4
•
Cohort
R G -1 0 1 in P la s m a
4
Hybridization-based HPLC-FL
• Linearity range:
• Plasma: 0.4–17000 ng/mL
• Urine: 170–17000 ng/mL
Geometric Mean Ratio
(%Reference)
[90% Confidence Interval]
AUC0-48hr
Cmax
2
Figure 1. Anti-miR-122 Treatment of HCV Infection
6
Bioanalytical Methodology:
Figure 2. RG-101 Plasma
Exposure Profiles: All Cohorts
and SAE Jaundice Patient
1
Table 4. Test vs. Reference Cohort Plasma PK
Exposure Comparisons for RG-101
2
Plasma (0–48hr)
Healthy Subjects
(Cohort 1, N=8)
Regimen
0
ESRD + HCV (8)
Tmax
(hr)
1
Plasma (0–48hr)
MRTlast
(hr)
8
ESRD (8)
Cmax
(µg/mL)
1
Healthy (8)
Plasma (0–48hr)
Urine (0–48hr)**
Cohort
AUC0-48hr
(µg*hr/mL)
6
Pharmacokinetics
Table 3. RG-101 Plasma PK Parameters Summary by Cohort
4
1*
(Reference)
2*
(Test)
3
(Test)
Subject (N)
Results
2
Cohort
and Michael
1
Huang
.5
1Regulus
1
Blem ,
0
Kai
1
Liu ,
M e a n ± S E (m g /m L )
John S.
1
Grundy ,
Cohort 1
Healthy
(N=8)
54.1 (11.8)
8 (100%)
Cohort 2
ESRD
(N=8)
54.5 (12.4)
8 (100%)
Cohort 3
ESRD + HCV
(N=8)
57.5 (8.5)
4 (50%)
55.4 (10.6)
20 (83.3%)
5 (62.5%)
2 (12.5%)
81.4 (15.7)
0.9 (0.17)
2 (25.0%)
6 (75.0%)
72.8 (17.0)
9.7 (3.25)
2 (25.0%)
5 (62.5%)
75.7 (12.2)
7.6 (1.72)
9 (37.5%)
13 (54.2%)
76.6 (14.9)
6.1 (4.34)
Total
(N=24)
Cohort 2
ESRD
(N=8)
Cohort 3
ESRD + HCV
(N=8)
Total
(N=24)
1 (12.5%)
8 (100.0%)
11 (45.8%)
1 (12.5%)
0
0
1 (12.5%)
0
0
0
3 (8.3%)
1 (12.5%)
4 (50.0%)
4 (50.0%)
1 (12.5%)
2 (25.0%)
0
6 (25.0%)
1 (4.2%)
4 (16.7%)
6 (25.0%)
1 (4.2%)
2 (8.3%)
0
*One subject experienced SAE of jaundice (considered related to study drug); one subject experienced anemia (unrelated)
**AEs rated as severe included: jaundice and anemia (same as SAEs noted above); upper abdominal pain
Note: One subject has 2 AEs missing ‘Severity, Relationship, and Seriousness’ info; which were accounted for as ‘Severe’, ‘Related to
study drug’, or ‘not included’, respectively, in this table
Conclusions
•
•
N/A
N/A
N/A
N/A
4 (50.0%)
1 (12.5%)
4 (50.0%)
1 (12.5%)
•
N/A
N/A
N/A
N/A
3 (37.5%)
4.91 (1.57)
3 (37.5%)
4.91 (1.57)
•
In all cohorts, RG-101 was rapidly absorbed and subsequently rapidly and extensively
cleared from plasma (presumably to tissues) within 24-hours post dose
Only relatively modest increases (<2-fold) in geometric mean plasma exposure measures of
RG-101 were observed in Cohorts 2 and 3, when compared to Cohort 1
The plasma PK findings from this study suggest little or no dose adjustment of RG-101 is
needed for HCV-infected renal impaired subjects
However, based on the SAE jaundice case reported in this study (and another previous
case in a RG-101 Phase 2 study), RG-101 is currently on FDA clinical hold until information
required to resolve the clinical hold has been satisfactorily provided by the Sponsor
The 67th Annual Meeting of the American Association for the Study of Liver Diseases · Hynes Convention Center, Boston · November 11-15, 2016