David Wyles, M.D., of the UC San Diego AntiViral Research Center, presents "HCV in 2015: New Medication Approvals and Innovative Studies...Including a One-Shot Cure?" at AIDS Clinical Rounds

1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance.
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AIDS CLINICAL ROUNDS

2. HCV in 2015: New medication approvals and innovative studies…including a one-shot cure?
David L. Wyles, MD

3. New approvals for 2015
1995
2000
2010
2005
2015
1989
HCV identified
Consensus IFN
IFN α-2a
IFN α-2b + RBV
Peg-IFNα-2b
Peg-IFNα-2a
HCV replicons
In vitro HCV replication
Peg-IFNα-2a
in HCV/HIV
IFN α-2b
BILN-2061
Phase 1b
0
20
40
60
80
100
SVR (%)
Relative misery
Boceprevir
Telaprevir
IFN-free GT1 DAA regimens
Sofosbuvir
Simeprevir (US)
Daclatasvir (EU)
You are here

4. What do we expect from new DAA regimens coming this fall?
22
122 Afdahl NEJM 2014. Kowdley NEJM 2014. Feld NEJM 2014. Poordad NEJM 2014. Manns M EASL 2014.
12 weeks; 1a and 1b
24 weeks; 1b only
63
8 weeks non-cirrhotic
99
96
94
90
94
96
82
86
91
87
0
20
40
60
80
100
SOF/LDV
3D-ABT/RBV
SOF/LDV
ASV/DCV
SVR12 (%)
Naïve
Experienced
Exp Cirrhotic

5. NEW REGIMENS IN HIV/HCV CO-INFECTION

6. PHOTON: SOF/RBV FOR HIV/HCV
•
Cirrhosis permitted
•Most ART allowed
–CD4>500 not on ART
–CD4>200 on ART
SOF/RBV (n=114)
SOF/RBV (n=68)
SOF/RBV (n=41)
GT1 TN
GT 2,3 TN
GT 2,3 TE
SOF/RBV (n=19)
SOF/RBV (n=55)
SOF/RBV (n=200)
GT 2,3 TE
GT 1,3,4 TN
GT 2 TN
12
36
Weeks
PHOTON-1
PHOTON-2 Naggie S. EASL 2014. Molina J-M. IAS 2014.

7. 76
88
67
92
94
85
89
91
83
86
0
20
40
60
80
100
GT1/4
GT2 TN
GT3 TN
GT2 TE
GT3 TE
SVR12 (%)
PHO-1
PHO-2
Naggie S. EASL 2014. Molina J-M. IAS 2014.
PHOTON: SOF/RBV FOR HIV/HCV
PHOTON 2: 65% (11/17) GT1 cirrhosis; 78% (18/23) GT 3 TE, cirrhosis

8. SOF/LDV in those with HIV Osinusi A. EASL 2014.
SOF/LDV
SOF/LDV
12
24
Weeks
Group 1 (n=13)
Group 2
(n=37)
FDC: SOF 400mg/LDV 90mg PO QD
•
Group 1: no ART
•
CD4>500 or HIV <500 with “stable” CD4
•
Group 2: CD4>100 and HIV <40
•
Allowed: EFV, RAL, or RPV
0
SVR12
Group 1
No ART
Group 2
ART
Male
54%
81%
African American
77%
86%
1a
75%
81%
F3
38%
22%
CD4
687
576

9. SOF/LDV in those with HIV Osinusi A. EASL 2014. Clinicaltrials.gov ION-4: NCT02073656
0
20
40
60
80
100
No ART
ART
SVR4
SVR12
12
22
10
SVR (%)
•
One HIV BT due to non-compliance, re-suppressed
•
Grade 3/4 AEs: neutropenia (1), AST (1), CPK (1)
•
Ongoing phase 3 study: ION-4

10. SVR12
ABT450/r/267 + 333 + R
ABT450/r/267 + 333 + R
12
24
Weeks
SVR12
N=31
N=32
•
Stable ART
–
ATV or RAL (part A)
–
HIV RNA <40 copies/mL
–
CD4 >200
Sulkowski M. IAS 2014. Eron JJ. ICAAC 2014.
12 Week
24 Week
Male
94%
91%
Naïve
65%
69%
Null
16%
16%
1a
87%
91%
F4
19%
19%
CD4
633
625
TURQUOISE I: 3D + RBV in HIV/HCV

11. TURQUOISE I: 3D + RBV in HIV/HCV Sulkowski M. IAS 2014. Eron JJ. ICAAC 2014.
94
94
97
0
20
40
60
80
100
SVR4
SVR12
SVR12 (%)
12wk
24 wk
•
2 Virologic failures
•
Both 1a cirrhotic null responders
•
Relapse 12 wk arm
•
BT at week 16
•
Well tolerated
•
No discontinuation due to AEs
•
5 HIV VL ≥40 copies/mL
•
None ≥200 copies/mL
•
All re-suppressed
•
DRV arms added (part B)
•
Phase 3 portion following
Full SVR12 data to be presented at AASLD. Wyles DL. #1939 AASLD 2014.

12. Scorecard: Which DAA regimen with which HAART regimen
SOF/RBV
SOF/SMV
SOF/LDV
SOF/DCV
3D/RBV
TDF/FTC/EFV
TDF/FTC/RPV
DRV/rit
No data
ATV/rit
No data
RAL
DTG
No data
No data
No data
No data
No data

13. What might the approvals look like?
Genotype 1:
•
SOF/LDV:
–
8 weeks naïve non-cirrhotic (non-HIV)
–
12 weeks all others
•
Mention of consideration to extend in experienced cirrhotics
–
Will have HIV indication
–
?Indication for other genotype?
•
3D +/- RBV
–
12 weeks naïve and most experienced
•
No RBV for GT 1b
•
24 weeks for 1a null responders with cirrhosis
–
Will have HIV indication
•
1b only: ASV/DCV

14. UPCOMING AND UNIQUE STUDIES: ACUTE HCV INFECTION

15. A5327: Sofosbuvir Plus Ribavirin Without Interferon For Treatment of Acute HCV in HIV-1 infected Individuals (SWIFT-C)
Historical SVR rate: 60%

16. A5327 Inclusion
•
HIV infected
–
CD4 >500 not on ART or deferred by pt/provider
–
On ART with HIV VL <50 and CD4 >200
•
Only ddI, D4T, and AZT exlcuded
•
Acute HCV (in the prior 6 months)
–
ALT>5x ULN or >250 U/L with documented normal in last year OR ALT >10x ULN if no prior or abnormal
•
Excluded if prior + AB
–
New + HCV RNA with documented – in last 6 months
–
Acute re-infection also eligible
•
Documented + AB with 2 negative HCV RNA (6 months apart) prior to reinfection
•
HBsAg negative

17. A5327
•
Cohort 1 closed to screening
–
16 on study
•
Opening of cohort 2 pending SVR4 results
–
To open 8 week arm:
•
90% CI around SVR4 lies entirely above 60%
•
14/17 will need to achieve SVR4
•
Powered based on assumption of 90% SVR12

18. UPCOMING AND UNIQUE STUDIES: WHAT’S GOING ON IN THE LIVER?

19. A5329: Interferon-Free Therapy for Chronic Hepatitis C Virus Genotype 1 Infection in Subjects with HIV-1 Coinfection Receiving Concurrent Antiretroviral Therapy
SVR12
ABT450/r/267 + 333 + R
RAL (N=25): ABT450/r/267 + 333 + R
12
24
Weeks
SVR12
DRV/r QD (N=25): ABT450/r/267 + 333 + R
SVR12
SVR12
ABT450/r/267 + 333 + R
8
RAL (N=25)
DRV/r QD (N=25)

20. Key Eligibility Criteria
•
Men and women age ≥ 18 to ≤ 70 years
•
On stable, qualifying antiretroviral regimen for at least 8 weeks prior to screening
–
Raltegravir 400 mg BID + Tenofovir 300 mg QD + Emtricitabine 200 mg QD or Lamivudine 300 mg QD
–
Darunavir 800mg mg QD + Ritonavir 100mg QD + Tenofovir 300 mg QD + Emtricitabine 200 mg QD or Lamivudine 300 mg QD
•
Modified to DRV 600mg BID + RIT 100mg BID after screening and > 2 weeks prior to entry
•
HIV-1 RNA < 50 copies/mL for ≥ 6 months; CD4+ count ≥200/mm3
•
No history of prior HIV-1 virologic failure during ART or documentation of HIV-1 genotypic resistance to any ARV
•
Chronic HCV genotype 1a or 1b infection
•
No prior HCV treatment 19

21. A5335s: Coinfected Subjects Treated with HCV Direct-Acting Antivirals Plus Ribavirin: Intrahepatic HCV Dynamics and Pharmacology: A Substudy of A5329

22. HCV at the level of a single cell Balagopal A. Gasto 2013.
The HCV viroscape

23. UPCOMING AND UNIQUE STUDIES: END-STAGE RENAL DISEASE

24. HCV and the kidney
•
Direct injury: MPGN +/- cryoglobulinemia
•
HCV contributes to insulin resistance and DM
•
High prevalence of HCV in those on HD
–
Increased risk for mortality
•
Bi-directional interaction in kidney transplant
–
Accelerated liver disease progression
–
Increased risk of post-transplant DM
–
Many studies show worse graft and pt survival

25. Curing HCV can prevent kidney disease Hsu Y-C. Hepatology 2014.

26. What do we know about new DAAs in patients with renal impairment?
Not much…
Sofosbuvir- uridine nucleotide analog
–
Major metabolite: GS-331007
–
Primarily renal excretion
–
Contraindicated in those with GFR <30
•
450% increase in AUC of GS-331007
Ledipasvir- NS5A inhibitor
–
Primarily eliminated in feces (>70% unchanged)
–
Limited (<2.0%) urinary excretion
Cornpropst M. #1101 EASL 2012. Kirby B. #O_22 HCV Clin Pharm Workshop 2013.

27. AbbVie 3D regimen in ESRD
•
All components: hepatic metabolism
–
<2% excreted in urine
•
RBV is renally cleared
–
200mg QD recommended dose for GFR <30 Ribavirin package insert.

28. An Open-Label Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT 450/Ritonavir and Dasabuvir with or without Ribavirin (RBV) in Treatment-Naïve Adults with Genotype 1 Chronic HCV Infection, with Severe Renal Impairment of ESRD (RUBY-1)
•
ABT-450/rit- Protease inhibitor
•
Ombitasvir- NS5A inhibitor
–
Co-formulated with ABT-450/rit
•
Dasabuvir- NS5B non-nucleoside inhibitor
•
3D regimen= OMB/450/r 2 tabs PO QD (25/150/100mg) + DAS 250mg PO BID

29. Schema and Objectives
•
Primary Objectives: Safety and Efficacy (SVR12)
•
Secondary: DAA PK, virologic breakthrough and relapse

30. Inclusion/Exclusion Criteria
Inclusion
•
HCV GT 1a or 1b
•
Treatment naïve
•
eGFR <30 mL/min/1.73m2 (MDRD method)
–
Stage 4: GFR 30-15
–
Stage 5: GFR <15 or HD
Exclusion
•
HIV-1 or HBV +
•
History of decompensated liver disease (CPT B or C)
•
Peritoneal Dialysis
•
Key laboratory exclusions
–
ALB <2.8 g/dL
–
Hgb <10.0 g/dL
–
PLT <25,000
–
Tbili >3.0 mg/dL
–
INR >2.3
Fibrosis stage determination: biopsy, FibroScan, or APRI/FibroSure

31. Study and PK assessments
•
Study duration 36 weeks
–
Weekly visits for first 4 weeks
•
Then q2wks to week 12
•
SVR4, SVR12, and SVR24 visits
–
Intensive PK at week4 and week4 + 1d
•
12 hour PK with 24 post-dose sample
•
Week 4: Stage 4 and Stage 5 non-dialysis day
•
+1d: Stage 5 dialysis day
–
Arterial and venous (pre/post-dialyzer samples)
–
Dialysate samples

32. Endpoints
•
Primary
–
SVR12
–
Rate of grade 3 or 4 adverse events
•
Secondary
–
Rates of on-treatment virologic failure
–
Relapse rates
–
PK parameters (AUC, Cmax/min, Tmax)

33. Timeline
•
Preliminary IRB approval: SEPT 3
•
UCSD SIV week of SEPT 22
–
8 slots (2 stage 4; 6 stage 5)
•
Screening to start ~ SEPT 29
•
Referrals:
–
David Wyles dwyles@ucsd.edu or 858-822-1779
–
Kathy Nuffer knuffer@ucsd.edu or 619-543-8129

34. UPCOMING AND UNIQUE STUDIES: THE “ONE-SHOT” CURE

35. A PHASE I/II, OPEN-LABEL DOSE ESCALATION STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SINGLE DOSES OF TT-034 IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) INFECTION

36. What is TT-034?
•
TT-034 is an RNAi therapeutic that is intended as a one-shot-monotherapy
–
Recombinant AAV genome delivered via an AAV8 vector (high liver tropism)
–
Continuously produces replenishing pool of shRNAs for over 180 days
–
shRNA target three separate, well conserved regions of HCV RNA genome
–
Capability for near complete hepatocyte coverage (transduction)

37. DNA
HCV (+) RNA
HCV
capsid replication complex
packaging
HCV (-) RNA
HCV (+) RNA
Viral proteins
TT-034
shRNA
B
shRNA-19
C
shRNA-6
ITR
A
shRNA-22
ITR
RISC
Dicer
Exportin 5
Viral RNA
No capsid
No replication complex
No packaging
MOA of TT-034 Against the HCV Infectious Cycle
Slide courtesy of David Suhy, PhD

38. TT-034 schematic
TT-034
p7
NS2
5’ UTR
3’ UTR
Structural Proteins
Non-Structural Proteins
C
NS3
E2
E1
NS4B
NS5A
NS4A
NS5B
ITR
ITR
A
shRNA-22
B
shRNA-19
C
shRNA-6 Lavender H AAC 2012.

39. Use of an AAV delivery system
ITR
ITR
A
shRNA-22
B
shRNA-19
C
shRNA-6
TT-033
Wildtype AAV8
REP/CAP removed and replaced with expression cassette
Recombinant AAV8
•
Non-integrating, non-pathogenic viral delivery system
•
Has been used in hundreds of patients in clinical trials
•
Sustained expression (months/years) of active drug following single injection
•
Differing AAV serotypes allow for tissue specific delivery
Slide courtesy of David Suhy, PhD

40. In vitro activity of TT-034
-20
0
20
40
60
80
100
1
100
10000
1000000
Rep 1b
Rep1a
HCVcc
vg/cell
HCV replicon
% signal inhibition
-20
0
20
40
60
80
100
100.00
10,000.00
1,000,000.00
vg/cell
JFH
JFH-808
% signal inhibition
Lavender H AAC 2012.

41. Activity against sequence variants
All isolates have >10%
Representation in the
database
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
—
+
—
+
—
—
—
—
—
—
—
—
+
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
+
+
+
+
++
+++
+
++
+
++
+
+
+++
—
++
++
—
shRNA6
shRNA19
shRNA22
Percent inhibition
Percent inhibition
Percent inhibition Lavender H AAC 2012.

42. Study Design and Objectives
•
Phase I/II, single-dose, dose escalation
–
Sequential dose cohorts (5)
–
Extensive safety monitoring
•
Staggered enrollment (6-10 weeks between subjects)
•
Primary Objective
–
Safety and tolerability
•
Secondary Objectives
–
Antiviral activity
–
Transduction efficiency
–
Dose selection (MTD/dose limiting toxicities)

43. Population and Dosing
•
HCV GT1, non-cirrhotic
–
Naïve or experienced
–
ALT <4x ULN
Cohort
Dose (vg/kg)
Dose escalation step (log 10)
Total No subjects
Dosing scheme for subjects
Observation period per subject and between cohorts before dose escalation
1
4.00 × 1010
Starting dose
2
Sequential (1+1)
6 week
2
1.25 × 1011
0.5
3
Sequential and parallel (1+2)
6 week
3
4.00 × 1011
0.5
3
Sequential and parallel (1+2)
6 week
4
1.25 × 1012
0.5
3
Sequential and parallel (1+2)
10 weeks
5
4.00 × 1012
0.5
3
Sequential and parallel (1+2)
10 weeks

44. Safety Criteria
•
High doses of vector in hemophilia study associated with ALT/AST elevation
–
Viral capsid response
•
Stopping criteria
–
Any death
–
Grade 3 or 4 toxicity possibly related to drug
–
ALT>10x baseline or >500 U/L
–
TB >2x ULN
–
INR >1.5
–
Other SAE possibly related to drug
•
Dose Limiting Toxicity Criteria
–
Single DLT grade 2- dose cohort may continue
–
Two DLT grade 2 or higher- cohort may continue if different DLT

45. Study status
•
Open now
•
High screen failure rate
–
Higher than expected prevalence of AAV-8 nAb
Please refer any HCV + adventurous souls!

46. UPCOMING AND UNIQUE STUDIES: STAY TUNED FOR MORE

47. One regimen to rule them all…
•
Next wave of pan-genotypic regimens
–
SOF/GS5816: ASTRAL studies
•
GT2 RCT with SOF/RBV- UCSD OCT 2014 (HCV mono)
•
GT1, 4, 5, 6 and GT 3 studies
–
ABT-493 + ABT-530
•
GT 2/3 – UCSD Fall/Winter 2014
•
GT 1 - ?
–
MK-5172 + MK-8742
•
Co-infected study enrolled (5 at UCSD)
•
Triple combination upcoming?

48. Acknowledgements
•
AVRC study and support staff
–
Joanne Santangelo
–
Kathy Nuffer
•
David Suhy, Tacere Therapeutics
•
Amber Faulise and Sharon Quigley (CTRI)
•
Owen Clinic Providers
–
Owen HCV clinic
•
Community HIV and HCV providers
•
UCSD Hepatology