UPDATE ON NEW AND UPCOMING DAA TREATMENT REGIMENS FOR HCV Andy Ustianowski

Lets briefly recap where we have come from and how we got here…

We didn’t realise there was a problem until relatively recently…

In the 1970s we recognised there was anon-­A non-­B hepatitis – but it was only in the very late 80s that we identified the cause…

1986 -­ First anti-­HCV efficacy demonstrated: ALT normalisation with IFN therapy

• Pilot study of 10 patients with non-­A, non-­B hepatitis received interferon-­α (IFNα) for up to 12 months

Hoofnagle JH, et al. N Engl J Med 1986;;315:1575–8

)ALT: alanine aminotransferase;;

AST: aspartate transaminase;; MU: million units

Normalisation of ALT and AST in a patient treated for 1 year with daily injections of recombinant human IFNα

1998 20022001 2011 2013

And it did get incrementally more effective..

Adapted from 1. Strader DB, et al. Hepatology 2004;;39:1147–71

NOTE: not a cross-­study comparison;; figure shows data from different heterogeneous studies

PEG-­IFN: pegylated interferon;; RBV: ribavirin

63–79

54–56

394234

166

91*

0

20

40

60

80

100

IFN6 mo1

IFN12 mo1

IFN/RBV6 mo1

IFN/RBV12 mo1

PEG-­IFN12 mo1

PEG-­IFN/ RBV12 mo1

PI/RBV/PEG-­IFN6-­12 mo2,3

SOF/RBV/PEG-­IFN3 mo5,6

1998 2002-­201120011986

Patients with SVR (%)

SMV/RBV/PEG-­IFN6-­12 mo4

8191*• Initially IFNα 3 MU 3 x per week for 6 months – 1 year

• Addition of RBV improved SVR• Pegylation increased drug exposure, permitting 1 x weekly dosing

We learnt lots about life cycle and targets for therapies

Feeney ER, Chung RT. BMJ 2014;;349:g3308;; Cell cycle adapted from Manns MP, et al. Nat Rev Drug Discov 2007;;6:991–1000 NUC: nucleos(t)ide

Protease inhibitorsNS5A inhibitors

NUC inhibitorsNon-­NUC inhibitors

Translation and

polyprotein processing

NS3/4protease inhibitors

Receptor binding and endocytosis Transport

and release

Virion assembly

RNA replication

Fusion and uncoating

(+) RNA

Membranous web

NS5B polymeraseinhibitors

Nucleos(t)ideNon-­nucleoside

NS5A inhibitorsreplication and assembly

Structural Non-­structural

Capsid shell

Envelope glycoproteins

Viral assembly

Protease Serine protease

Membranous web formation

RNA dependent RNA polymerase

Viral replication or assembly

Directly Acting Antivirals (DAAs)

DAAs, in four classes, are now licensed

1. Merck, Sharp & Dohme Ltd. VICTRELIS (boceprevir), SmPc July 2011;; 2. Janssen Cilag International. INCIVO (telaprevir), SmPC, September 2011;; 3. AbbVie Ltd. VIEKIRAX(ombitasvir/paritaprevir/ritonavir), SmPC, January 2015;; 4. AbbVie Ltd. EXVIERA(dasabuvir), SmPC, January 2015;; 5. Gilead Sciences Europe Ltd. SOVALDI (sofosbuvir), SmPC, March 2015;; 6. Janssen Cilag International. OLYSIO(simeprevir), SmPC, May 2014;; 7. Bristol-­Myers Squibb Pharma. Daklinza (daclatasvir), SmPC, August 2014;; 8. Gilead Sciences Europe Ltd. HARVONI(ledipasvir/sofosbuvir), SmPC, November 2014

BOC: boceprevir;; DAA: direct-­acting antiviral agent;; DCV: daclatasvir;; DSV: dasabuvir;; LDV: ledipasvir;;

OMV: ombitasvir;; PTV: paritaprevir;; PEG-­IFN: pegylated interferon;; RBV: ribavirin;; RTV: ritonavir ;; SmPC: Summary of Product

Characteristics;; SMV: simeprevir;; SOF: sofosbuvir;; TVR: telaprevir

Treatment duration(weeks)

28–48

12–48

24

12–24

12

12–24

12–24

12–24

8–24

+ PEG-­IFN + RBV

+ RBV

+ SMV

BOC + PEG-­IFN + RBV

TVR + PEG-­IFN + RBV

SOF

SOF

SOF

+ DCVSOF

LDVSOF

+ RBVPTV/RTVOMV DSV+

± RBV

± RBV

± RBV

SMV + PEG-­IFN + RBV

And we can use some of them in some patients…

HCV – further improvements in efficacy…

Data based on G1: Adapted from 1. Strader DB, et al. Hepatology 2004;;39:1147–71;; 2. INCIVEK [PI]. Cambridge, MA:, 2013;; 3. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co, 2014;; 4. Manns M, et al. EASL 2013;; Oral #1413;; 5. Ustianowski – personal communication

NOTE: not a cross-­study comparison;; figure shows data from different heterogeneous studies

DAA: direct-­acting antiviral agent;; PI: protease inhibitor;;

SMV: simeprevir

1998 20022001 2011 2013

63–79

54–56

394234

166

91*

0

20

40

60

80

100

IFN6 mo1

IFN12 mo1

IFN/RBV6 mo1

IFN/RBV12 mo1

PEG-­IFN12 mo1

PEG-­IFN/ RBV12 mo1

PI/RBV/PEG-­IFN6–12 mo2,3

All Oral DAA

Regimens3 mo5

1998 20022001 2011 20131986

SMV/RBV/PEG-­IFN6–12 mo4

8195+

Patients with SVR (%)

Now

The ‘hard to treat’ genotype with the highest ‘unmet medical need’ has become G3

Where might we use them?

P/R SOF/R SOF/P/R SOF/LDV* SOF/DCV* Abbvie3D*

G1

G2

G3

G4

G5

* = +/-­ RBVPersonal communication – A Ustianowski

Much of the data comes from mono-­infected studies…

Arends et al., J Hepatology 2015

Similar response rates in HIV/HCV co-­infected and HCV mono-­infected patients treated with SOF + PEG-­IFN + RBV (12 weeks) (Study 1910)

• SOF was well tolerated in patients taking a wide variety of HIV ART regimens without any additive effects to the expected safety profile of PEG-­IFN + RBV

Lawitz E, et al. APASL 2013;; Oral #LB-­02;; Rodriguez-­Torres M, et al. IDWeek 2013;; Poster #714 ART: antiretroviral therapy;; SOF: sofosbuvir;; SVR: sustained virological response

21/23296/327Patients with SVR12 (%) 90 91

0

20

40

60

80

100

NEUTRINO (HCV mono-­infected)

Study 1910 (HIV/HCV co-­infected)

21/23295/327

PHOTON-­2: High SVR in adult patients with HIV/HCV co-­infection treated with SOF + RBV

• Therapy was well tolerated, with a low rate (2%) of discontinuation of HCV treatment due to adverse events

Molina JM, et al. Lancet 2015;;385:1098–106 SOF: sofosbuvir;; SVR: sustained virological response

85 8983 86

0

20

40

60

80

100

GT 1 GT 2 GT 2 GT 3

SVR12 (%)

Treatment-­naïve Treatment-­experienced

12 weeks

24 weeks

SOF + RBV

95/112 17/19 5/6 42/49

ION-­4: High SVR in adult GT 1 and GT 4 patients with HIV/HCV co-­infection treated with 12 weeks’ LDV/SOF

Naggie S, et al. CROI 2015. Oral #LB-­152

Naïve vs Experienced Cirrhosis statusOverall

95 97

0

20

40

60

80

100 96 94

0

20

40

60

80

10096

0

20

40

60

80

100

LDV/SOF 12 Weeks

ExperiencedNaïve No cirrhosis Cirrhosis

321/335 142/150 179/185 63/67258/268

SVR12 (%)

LDV + SOF for 24 weeks should be considered for patients with compensated cirrhosisLDV + SOF for 12 weeks may be considered in patients with cirrhosis deemed at low risk for clinical

disease progression and who have subsequent retreatment optionsLDV: ledipasvir;; SOF: sofosbuvir;; SVR: sustained virological response

ALLY-­2: High SVR in adult patients with HIV/HCV co-­infection treated with 12 weeks’ SOF + DCV: Genotypes 1–4

Wyles D, et al. CROI 2015;; Oral: #LB-­151 DCV: daclatasvir;; SOF: sofosbuvir;; SVR: sustained virological response

97 98

0

20

40

60

80

100

SOF + DCV Treatment-­naïve

SOF + DCV Treatment-­experienced

SVR 12 (%)

51/5298/101

TURQUOISE-­1: High SVR in adult patients with HIV/HCV co-­infection treated with 12 weeks’ OMV/PTV/RTV + DSV + RBV

Sulkowski MS, et al. JAMA 2015;;313:1223–31

TURQUOISE-­1 included treatment-­naïve and treatment-­experienced patients and patients with and without cirrhosis.

AE: adverse event;; DSV: dasabuvir;; OMV: ombitasvir;; PTV: paritaprevir;; RBV: ribavirin;; RTV: ritonavir;; SVR: sustained virological response

94 91

0

20

40

60

80

100

OMV/PTV/RTV + DSV + RBV 12 weeks

OMV/PTV/RTV + DSV + RBV 24 weeks

29/3229/31

SVR12 (%

)

So – we have the same algorithm for HCV and HIV/HCV infected

But remember:• Potential drug-­interactions…• Some caveats with the co-­infected data

GMEC ODN Guidance Feb 2016

What’s coming…?

HCV NS5A inhibitor, 50 mg

Elbasvir(MK-8742)

HCV NS3/4A inhibitor, 100 mg

Grazoprevir(MK-5172)

Rockstroh et al. AASLD 2015. Abstract 210

Rockstroh et al. AASLD 2015. Abstract 210

Compared to mono-­infected?

0%

25%

50%

75%

100%

SVR, %

HCV/HIV coinfected HCV monoinfected All

261/277

573/609

834/886

Total

94.2% 94.1% 94.1%

*Primary endpoint: SVR12 (HCV RNA <15 IU/mL)

EBR/GZR

233/248

478/504

711/752

94.0% 94.8% 94.5%

28/29

95/105

123/134

96.6% 90.5% 91.8%

EBR/GZR+RBV

Nelson et al., ID Week 2015, Presentation 1267

SOF/Velpatasvir -­ BackgroundSOF Nucleotide NS5B polymerase inhibitor

OO N

NH

O

O

PO

HN

O

O

OH3C

H3C

CH3HO F

CH3 ♦ Sofosbuvir (SOF)1,2‒ Potent antiviral activity against HCV GT 1‒6

‒ Once-­daily, oral, 400-­mg tablet

SOF VEL

VELNS5A inhibitor

♦ Velpatasvir (VEL;; GS-­5816)3-­5– Picomolar potency against GT 1‒6– 2nd-­generation inhibitor with improved resistance profile

♦ SOF/VEL Single Tablet Regimen (STR)– Once daily, oral, STR (400/100 mg)

1. Jacobson IM, et al. N Engl J Med 2013;;368:1867-­ 77;; 2. Lawitz E, et al. N Engl J Med 2013;;368:1878-­87;; 3. Cheng G, et al. EASL 2013, poster 1191;; 4. German P, et al. EASL 2013, poster 1195;; 5. Lawitz E, et al. EASL 2013, poster 1082.

23

EC50 Comparison of NS5A Inhibitors Against GT 1-­6 HCV

• Velpatasvir has low EC50 across HCV genotypes 1-­6

Data on File, Gilead Sciences, Inc.

EC50Values in Genotype 1-­6 Replicons, nM

1a 1b 2a 2a* 2b 2b* 3a 4a 5a 6a 6e

Velpatasvir 0.014 0.016 0.008 0.016 0.002 0.006 0.004 0.009 0.054 0.006 0.13

Ledipasvir 0.031 0.004 21 249 16 530 168 0.39 0.15 1.1 264

Daclatasvir 0.063 0.016 0.047 19.7 0.006 9.8 0.15 0.015 0.071 0.031 >28.5

1. Values represent the geometric mean from at least three independent experiments in either automated 96-­well or 384-­well format2. HCV strains: 1a: H77;; 1b: Con-­1;; 2a: JFH-­1;; 2a*: J6;; 2b: MD2b8;; 2b*: MD2b-­1;; 3a: S52;; 4a: ED43;; 5a: SA13;; 6a: HK6;; 6e: D883. 2a* and 2b* replicons encode the dominant M31 polymorphic residue in NS5A, and represent approximately 85% and 75% of the

polymorphism within each subtype in the EU HCV database, respectively4. Genotype 1a, 1b, 2a, 4a and 6a are authentic and stable subgenomic replicons, and genotype 3a is an authentic but transiently transfected

replicon5. Genotype 2a*, 2b, 2b*, 5a and 6e are NS5A chimeric and transiently transfected replicons6. NS5A chimeric replicons either encoding full-­length NS5A (2a*, 2b and 2b*) or NS5A amino acids 9-­184 (5a and 6e)7. Source: Studies PC-­281-­2024, PC-­256-­2037, and PC-­281-­2007

99 9995 100 97 100 98

0

20

40

60

80

100

SVR12 (%

)

Total

10151035

323328

264277

116116

3435

4141

237238

GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

Feld, AASLD, 2015, LB-­2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610. Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med. 2015. DOI: 10.1056/NEJMoa1512612. Mangia, AASLD, 2015, 249. Foster GR, et al. New Engl J Med. 2015. DOI: 10.1056/NEJMoa1512612.

Pooled ASTRAL Studies (ASTRAL-­1, ASTRAL-­2, ASTRAL-­3)

SOF/VEL STR for 12 Weeks: SVR12

25

26

SVR12 by GenotypeASTRAL-­1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-­Infected Patients

Feld, AASLD, 2015, LB-­2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610

99 98 99 100 100 97 100

0

20

40

60

80

100

SVR12 (%

)

618/624

Total

206/210 117/118 104/104 116/116 34/35 41/41

1a 1b 2 4 5 6

Genotype

1 relapse2 LTFU1 WC

1 relapse 1 death

LTFU=lost to follow up;; WC=withdrew consent

‡

SVR12 by Cirrhosis Status or Treatment History

ASTRAL-­1: SOF/VEL STR for 12 Weeks in GT 1, 2, 4, 5, 6 HCV-­Infected Patients

Error bars represent 95% confidence intervals.Feld, AASLD, 2015, LB-­2. Feld JJ, et al. N Engl J Med. 2015. DOI: 10.1056/NEJMoa1512610

99 99 99 99 99

0

20

40

60

80

100

SVR12 (%

)

618/624 496/501 120/121 418/423

Non-­Cirrhotic Treatment-­Naïve

Treatment-­Experienced

200/201

Total Cirrhotic

And in HIV/HCV Co-­Infection?Astral 5….

95% SVR• 100% (19/19) in cirrhotics• 97% (28/29) in TE

EASL 2016, PS 104

So – what do I think we should be using by end of the year in HIV/HCV co-­infected?

Genotype and Prior Experience

Regimen Non-­Cirrhotic Cirrhotic Decompensated Cirrhotic

G1 Naïve &P/R experienced

SOF/LDV 8 weeks* N,S or12 weeks N2,S

+R for 12 weeks N1,E-­R for 24 weeks S

+R for 12 weeks E,S4

OBV/PTV/r+DBV

GT1a: +R 12 weeks N,SGT1b: 12 weeks N,S

GT1a: +R 24 weeks N,SGT1b: +R 12 weeks N,S

GZR/EBRU 12 weeksSOF/VELU 12 weeks +R for 12 weeks

DAA experiencedX SOF/LDV 12 weeks N +R for 12 weeks N1,E +R for 12 weeks E,S4 -­R for 24 weeks S9SOF/P/R 12 weeks N,S

G2 Naïve SOF/R 12 weeks N,S 12-­24 weeks§ N,S1 24 weeks SSOF/P/R 12 weeks

P/R experienced &DAA experiencedX

SOF/R 12 weeks N,S 12-­24 weeks§ N,S 24 weeks SSOF/P/R 12 weeks SSOF/VELU 12 weeks 12 weeks

G3 Naïve &ExperiencedX

SOF/P/R 12 weeks N8,SSOF/DCV 12 weeks N6 +R for 12 weeks N7,S4 +R for 12 E -­24 weeks§ -­R for 24 weeks

SOF/VELU 12 weeks +R for 12 weeksG4 Naïve &

P/R ExperiencedSOF/LDV 12 weeks N2,S 12 weeks N3, S4 +R for 12 weeks E,S4OMB/PTV/r +R for 12 weeks NS +R for 12 weeks S4,N4SOF/DCV 12 weeks N5,S5GZR/EBRU 12 weeksSOF/VELU 12 weeks 12 weeks

DAA experiencedX SOF/LDV 12 weeks N3,SSOF/DCV +R for 12 weeks N5,S5GZR/EBRU 12 weeksSOF/VELU 12 weeks 12 weeks

G5/6 Naïve & ExperiencedX

SOF/P/R 12 weeks S

SOF/LDV 12 weeks +R for 12 weeks +R for 12 weeks -­R for 24 weeksSOF/VELU 12 weeks

Ustianowski & Wilkins – personal thoughts

And what about after all this?

Company NS3/4 NS5A NS5B NucAbbvie 493 530Gilead 9857 Velpatasvir SofosbuvirMSD 5172 8408 / 8742 3682

These doubles/triples just for failures or first-­line??