recent hcv treatment developments: in pursuit of perfectovir professor greg dore kirby institute,...
TRANSCRIPT
Recent HCV treatment developments:In pursuit of perfectovir
Professor Greg DoreKirby Institute, UNSW Australia;
& St Vincent’s Hospital, Sydney
20132011 20152012 20162014
IFN-free DAA combination
PEG-IFN + RBV
PEG-IFN + RBV + DAA Treatment complexity
HCV treatment strategies: Australia
Dore GJ. MJA 2012 (revised)
20132011 20152012 20162014
IFN-free DAA combination
PEG-IFN + RBV
PEG-IFN + RBV + DAA Treatment complexity
HCV treatment strategies: United States
Dore GJ. MJA 2012 (revised)
HCV life cycle
Liang TJ & Ghany MG. NEJM 2013;368:1907-1917
HCV therapeutic development
Welsch & Zeuzum. Gastroenterology 2012;142:1351-1355
X
?
X
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
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)
HCV therapeutic development
GT1 (n=292) GT4 (n=28) GT5/6 (n=7) Cirrhosis (n=54)0
10
20
30
40
50
60
70
80
90
100
SVR12 %
NEUTRINO: PEG-IFN/RBV/Sofosbuvir
Genotype 1 (+4/5/6) treatment naïve, 12 weeks
Lawitz E et al. NEJM 2013;368:1878-1887
Se-ries1
0
10
20
30
40
50
60
70
80
90
100
GT1 naive (+RBV 12 wks, n=473)
GT1 exp (+RBV 12 wks, n=297)
GT1b exp (+RBV 12 wks, n=88)
GT1b exp (12 wks, n=91)
GT1b naïve (+RBV 12 wks, n=210)
GT1b naïve (12 wks, n=209)
GT1a naïve (+RBV 12 wks, n=100)
GT1a naïve (12 wks, n=205)
GT1 cirrhosis (+RBV 12 wks, n=208)
GT1 cirrhosis (+RBV 24 wks, n=172)
SVR12 %
Abbvie: ABT-450/r/Ombitasvir/Dasabuvir
Genotype 1, treatment naïve and experienced
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
Se-ries1
0
10
20
30
40
50
60
70
80
90
100
GT1 naïve (12 wks, n=214)
GT1 naïve (+RBV, 12 wks, n=217)
GT1 exp (12 wks, n=109)
GT1 exp (+RBV, 12 wks, n=111)
GT1 exp (24 wks, n=109)
GT1 exp (+RBV, 24 wks, n=111)
GT1 naive (8 wks, n=215)
GT1 naive (+RBV 8 wks, n=216)
GT1 naive (12 wks, n=216)
SVR 12 %
Genotype 1, treatment naive and experienced
Afdhal N, et al. NEJM 2014;370:1483-1493; Afdhal N, et al. NEJM 2014; Kowdley KV, et al. NEJM 2014
ION-1
(16% cirrhosis)
ION-2
(20% cirrhosis)
ION-3
Gilead: Sofosbuvir/Ledipasvir
Series10
10
20
30
40
50
60
70
80
90
100
GT1 null F0-2 (n=14)
GT1 naïve/null F3-4 (n=14)
GT1 null F0-2 (+RBV, n=27)
GT1 naïve/null F3-4 (+RBV, n=27)
SVR 12 %
Genotype 1, treatment naive and experienced, 12 weeks
Jacobson I, et al. AASLD 2013
COSMOS: Sofosbuvir/Simeprevir
SOF/RBV (n=70) PEG/RBV (n=67)0
10
20
30
40
50
60
70
80
90
100
SVR 12 %
Sofosbuvir/Ribavirin vs PEG-IFN/RBV
Genotype 2, treatment naive, 12 weeks vs 24 weeks
Lawitz E et al. NEJM 2013;368:1878-1887
Series10
10
20
30
40
50
60
70
80
90
100
F0-3 (Naïve, n=92) F4 (Naïve, n=13) F0-3 (Exp, n=100) F4 (Exp, n=45)
SVR 12 %
Zeuzem S et al, AASLD 2013
Sofosbuvir/Ribavirin
Genotype 3, treatment naïve and experienced, 24 weeks
Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
HCV prevalence and genotype distribution
Hajarizadeh B, Grebely J, Dore GJ. Nat Rev Gastroenterol Hepatol 2013
Series10
10
20
30
40
50
60
70
80
90
100
GT1 (n=55) GT2 (n=21)
GT3 (n=54) GT4/5/6 (n=23)
SVR12 %
Everson GT, et al. ILC2014
Sofosbuvir/GS-5816
Treatment naïve, F0-3, 12 weeks
Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
0
10
20
30
40
50
60
70
80
90
100
12 wks FDC ( n=19)
SVR 12 %
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
0
10
20
30
40
50
60
70
80
90
100
12 wks FDC ( n=19) 8 wks FDC/RBV (n=21) 8 wks FDC (n=19)
SVR 12 %
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
0
10
20
30
40
50
60
70
80
90
100
12 wks FDC ( n=19) 8 wks FDC/RBV (n=21) 8 wks FDC (n=19) 6 wks FDC/RBV (n=25)
SVR 12 %
Lawitz E et al, AASLD 2013; Gane E et al, AASLD 2013
Sofosbuvir/Ledipasvir
Genotype 1, treatment naïve, F0-2
0
10
20
30
40
50
60
70
80
90
100
12 wks FDC (n=20)
SVR 12 %
Genotype 1, treatment naïve, F0-3
Kohli A et al, AASLD 2013
Sofosbuvir/Ledipasvir/3rdDAA
0
10
20
30
40
50
60
70
80
90
100
12 wks FDC (n=20) 6 wks FDC/GS-9669 (n=20) 6 wks FDC/GS-9451 (n=20)
SVR12 %
Kohli A et al, AASLD 2013
Sofosbuvir/Ledipasvir/3rdDAA
Genotype 1, treatment naïve, F0-3
HCV regimen approval timelines: Australia
2020
PEG + RBV
20162014 20182015 20192017
PEG + RBV + TPV/BCP
HCV regimen approval timelines: Australia
2020
PEG + RBV
20162014 20182015 20192017
PEG + RBV + TPV/BCP
PEG + RBV + Sofosbuvir / Simeprevir (G1)PBACTGA
IFN-free: Sofosbuvir + Ribavirin (G2/3)PBACTGA
HCV regimen approval timelines: Australia
2020
PEG + RBV
20162014 20182015 20192017
PEG + RBV + TPV/BCP
PEG + RBV + Sofosbuvir / Simeprevir (G1)PBACTGA
IFN-free: Sofosbuvir + Ribavirin (G2/3)PBACTGA
IFN-free: ABT450/r + Ombitasvir + Dasabuvir +/- Ribavirin (G1)
IFN-free: Sofosbuvir + Ledipasvir (G1)TGA PBAC
TGA PBAC
HCV regimen approval timelines: Australia
2020
PEG + RBV
20162014 20182015 20192017
PEG + RBV + TPV/BCP
PEG + RBV + Sofosbuvir / Simeprevir (G1)PBACTGA
IFN-free: Sofosbuvir + Ribavirin (G2/3)PBACTGA
IFN-free: ABT450/r + Ombitasvir + Dasabuvir +/- Ribavirin (G1)
IFN-free: Sofosbuvir + Ledipasvir (G1)TGA PBAC
TGA PBAC
IFN-free: Sofosbuvir + GS-5816 (GT1-6)TGA PBAC
HCV regimen approval timelines: Australia
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
HCV therapeutic development