in pursuit of perfectovir!

Report
Recent HCV treatment developments:
In pursuit of perfectovir
Professor Greg Dore
Kirby Institute, UNSW Australia;
& St Vincent’s Hospital, Sydney
HCV treatment strategies: Australia
PEG-IFN + RBV
PEG-IFN + RBV + DAA
Treatment complexity
IFN-free DAA combination
2011
2012
2013
2014
2015
2016
Dore GJ. MJA 2012 (revised)
HCV treatment strategies: United States
PEG-IFN + RBV
PEG-IFN + RBV + DAA
Treatment complexity
IFN-free DAA combination
2011
2012
2013
2014
2015
2016
Dore GJ. MJA 2012 (revised)
HCV life cycle
Liang TJ & Ghany MG. NEJM 2013;368:1907-1917
HCV therapeutic development
X
X
?
Welsch & Zeuzum. Gastroenterology 2012;142:1351-1355
Key recent HCV therapeutic development findings:
•
Sofosbuvir (nucleotide analogue) and Simeprevir (protease
inhibitor) licensure for GT1 has revealed the future = IFN-free
dual DAA short duration therapy (12 weeks)
•
Several highly curative GT1 IFN-free DAA regimens will be
available
•
HCV GT3 therapeutic solution less advanced, but pangenotypic
regimens likely
•
HIV does not impair response to IFN-free DAA therapy
•
HCV resistance will not be a major clinical issue
•
Ultimately limited individualisation required
HCV therapeutic development
Key attributes of perfectovir
•
Extremely high efficacy (>95%)
•
Minimal toxicity
•
Once daily dosing
•
Pangenotypic
•
Short duration (4-6 weeks)
HCV therapeutic development
Key attributes of perfectovir
•
Extremely high efficacy (>95%)
•
Minimal toxicity
•
Once daily dosing
•
Pangenotypic
•
Short duration (4-6 weeks)
NEUTRINO: PEG-IFN/RBV/Sofosbuvir
Genotype 1 (+4/5/6) treatment naïve, 12 weeks
100
90
80
70
60
SVR12
%
50
40
30
20
10
0
GT1 (n=292)
GT4 (n=28)
GT5/6 (n=7)
Cirrhosis (n=54)
Lawitz E et al. NEJM 2013;368:1878-1887
Abbvie: ABT-450/r/Ombitasvir/Dasabuvir
Genotype 1, treatment naïve and experienced
100
GT1 naive (+RBV 12 wks, n=473)
90
GT1 exp (+RBV 12 wks, n=297)
80
GT1b exp (+RBV 12 wks, n=88)
70
GT1b exp (12 wks, n=91)
60
SVR12
%
GT1b naïve (+RBV 12 wks, n=210)
50
GT1b naïve (12 wks, n=209)
40
GT1a naïve (+RBV 12 wks, n=100)
30
GT1a naïve (12 wks, n=205)
20
GT1 cirrhosis (+RBV 12 wks, n=208)
10
GT1 cirrhosis (+RBV 24 wks, n=172)
0
Sapphire-I & II
Pearl-II & III
Pearl-IV & Turquoise-II
Zeuzem S, et al. NEJM 2014;370:1604-1614; Poordad F, et al. NEJM 2014; Feld JJ, et al. NEJM 2014
Gilead: Sofosbuvir/Ledipasvir
Genotype 1, treatment naive and experienced
100
SVR 12
%
90
GT1 naïve (12 wks, n=214)
80
GT1 naïve (+RBV, 12 wks, n=217)
70
GT1 exp (12 wks, n=109)
60
GT1 exp (+RBV, 12 wks, n=111)
50
GT1 exp (24 wks, n=109)
40
GT1 exp (+RBV, 24 wks, n=111)
30
GT1 naive (8 wks, n=215)
20
GT1 naive (+RBV 8 wks, n=216)
10
GT1 naive (12 wks, n=216)
0
ION-1
ION-2
(16% cirrhosis)
(20% cirrhosis)
ION-3
Afdhal N, et al. NEJM 2014;370:1483-1493; Afdhal N, et al. NEJM 2014; Kowdley KV, et al. NEJM 2014
COSMOS: Sofosbuvir/Simeprevir
Genotype 1, treatment naive and experienced, 12 weeks
100
90
80
GT1 null F0-2 (n=14)
70
60
SVR 12
%
GT1 naïve/null F3-4 (n=14)
50
40
GT1 null F0-2 (+RBV, n=27)
30
20
GT1 naïve/null F3-4 (+RBV, n=27)
10
0
Jacobson I, et al. AASLD 2013
Sofosbuvir/Ribavirin vs PEG-IFN/RBV
Genotype 2, treatment naive, 12 weeks vs 24 weeks
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
SOF/RBV (n=70)
PEG/RBV (n=67)
Lawitz E et al. NEJM 2013;368:1878-1887
Sofosbuvir/Ribavirin
Genotype 3, treatment naïve and experienced, 24 weeks
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
F0-3 (Naïve, n=92)
F4 (Naïve, n=13)
F0-3 (Exp, n=100)
F4 (Exp, n=45)
Zeuzem S et al, AASLD 2013
HCV therapeutic development
Key attributes of perfectovir
•
Extremely high efficacy (>95%)
•
Minimal toxicity
•
Once daily dosing
•
Pangenotypic
•
Short duration (4-6 weeks)
HCV prevalence and genotype distribution
Hajarizadeh B, Grebely J, Dore GJ. Nat Rev Gastroenterol Hepatol 2013
Sofosbuvir/GS-5816
Treatment naïve, F0-3, 12 weeks
100
90
80
SVR12
%
70
GT1 (n=55)
60
GT2 (n=21)
50
GT3 (n=54)
40
GT4/5/6 (n=23)
30
20
10
0
Everson GT, et al. ILC2014
HCV therapeutic development
Key attributes of perfectovir
•
Extremely high efficacy (>95%)
•
Minimal toxicity
•
Once daily dosing
•
Pangenotypic
•
Short duration (4-6 weeks)
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
12 wks FDC ( n=19)
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
12 wks FDC ( n=19)
8 wks FDC/RBV (n=21)
8 wks FDC (n=19)
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
12 wks FDC ( n=19)
8 wks FDC/RBV (n=21)
8 wks FDC (n=19)
6 wks FDC/RBV (n=25)
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
Sofosbuvir/Ledipasvir/3rdDAA
Genotype 1, treatment naïve, F0-3
100
90
80
70
60
SVR 12
%
50
40
30
20
10
0
12 wks FDC (n=20)
Kohli A et al, AASLD 2013
Sofosbuvir/Ledipasvir/3rdDAA
Genotype 1, treatment naïve, F0-3
100
90
80
70
60
SVR12
%
50
40
30
20
10
0
12 wks FDC (n=20)
6 wks FDC/GS-9669 (n=20)
6 wks FDC/GS-9451 (n=20)
Kohli A et al, AASLD 2013
HCV regimen approval timelines: Australia
HCV regimen approval timelines: Australia
PEG + RBV + TPV/BCP
PEG + RBV
2014
2015
2016
2017
2018
2019
2020
HCV regimen approval timelines: Australia
TGA
PBAC
IFN-free: Sofosbuvir + Ribavirin (G2/3)
TGA
PBAC
PEG + RBV + Sofosbuvir / Simeprevir (G1)
PEG + RBV + TPV/BCP
PEG + RBV
2014
2015
2016
2017
2018
2019
2020
HCV regimen approval timelines: Australia
TGA
PBAC
IFN-free: Sofosbuvir + Ledipasvir (G1)
TGA
PBAC
IFN-free: ABT450/r + Ombitasvir + Dasabuvir +/- Ribavirin (G1)
TGA
PBAC
IFN-free: Sofosbuvir + Ribavirin (G2/3)
TGA
PBAC
PEG + RBV + Sofosbuvir / Simeprevir (G1)
PEG + RBV + TPV/BCP
PEG + RBV
2014
2015
2016
2017
2018
2019
2020
HCV regimen approval timelines: Australia
TGA
PBAC
IFN-free: Sofosbuvir + GS-5816 (GT1-6)
TGA
PBAC
IFN-free: Sofosbuvir + Ledipasvir (G1)
TGA
PBAC
IFN-free: ABT450/r + Ombitasvir + Dasabuvir +/- Ribavirin (G1)
TGA
PBAC
IFN-free: Sofosbuvir + Ribavirin (G2/3)
TGA
PBAC
PEG + RBV + Sofosbuvir / Simeprevir (G1)
PEG + RBV + TPV/BCP
PEG + RBV
2014
2015
2016
2017
2018
2019
2020
HCV therapeutic development
A few caveats
•
High drug pricing
•
Probable disease stage restriction for IFN-free DAA therapy
•
Potential treatment caps
But
•
Several pharma companies should ensure competitive pricing
•
Ability to cure close to 100% should empower the sector

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