View
3
Download
0
Category
Preview:
Citation preview
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??
Recommended