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AIDS CLINICAL ROUNDS

HCV in 2015: New medication approvals and innovative

studies…including a one-shot cure?

David L. Wyles, MD

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

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

SVR1

2 (%

)

NaïveExperiencedExp Cirrhotic

NEW REGIMENS IN HIV/HCV CO-INFECTION

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

PHO

TON

-1

PHO

TON

-2

Naggie S. EASL 2014. Molina J-M. IAS 2014.

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

SVR1

2 (%

)

PHO-1PHO-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

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

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 SV

R (%

)

• 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

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

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

SVR1

2 (%

) 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.

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

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

UPCOMING AND UNIQUE STUDIES: ACUTE HCV INFECTION

A5327: Sofosbuvir Plus Ribavirin Without Interferon For Treatment of

Acute HCV in HIV-1 infected Individuals (SWIFT-C)

Historical SVR rate: 60%

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

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

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

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)

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

A5335s: Coinfected Subjects Treated with HCV Direct-Acting Antivirals Plus Ribavirin: Intrahepatic HCV Dynamics

and Pharmacology: A Substudy of A5329

HCV at the level of a single cell

Balagopal A. Gasto 2013.

The HCV viroscape

UPCOMING AND UNIQUE STUDIES: END-STAGE RENAL DISEASE

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

Curing HCV can prevent kidney disease

Hsu Y-C. Hepatology 2014.

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.

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.

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

Schema and Objectives

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

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

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

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)

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

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

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

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)

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

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.

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

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

% s

igna

l inh

ibiti

on

-20

0

20

40

60

80

100

100.00 10,000.00 1,000,000.00

vg/cell

JFH

JFH-808

% s

igna

l inh

ibiti

on

Lavender H AAC 2012.

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

Perc

ent i

nhib

ition

Pe

rcen

t inh

ibiti

on

Perc

ent i

nhib

ition

Lavender H AAC 2012.

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)

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

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

Study status

• Open now • High screen failure rate

– Higher than expected prevalence of AAV-8 nAb

Please refer any HCV + adventurous souls!

UPCOMING AND UNIQUE STUDIES: STAY TUNED FOR MORE

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?

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