Recent HCV treatment developments: In pursuit of perfectovir
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Recent HCV treatment developments:In pursuit of perfectovir
Professor Greg DoreKirby Institute, UNSW Australia;
& St Vincent’s Hospital, Sydney
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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)
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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)
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HCV life cycle
Liang TJ & Ghany MG. NEJM 2013;368:1907-1917
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HCV therapeutic development
Welsch & Zeuzum. Gastroenterology 2012;142:1351-1355
X
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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
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Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
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Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
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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
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Se-ries1
0
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60
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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
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Se-ries1
0
10
20
30
40
50
60
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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
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Series10
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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
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SOF/RBV (n=70) PEG/RBV (n=67)0
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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
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Series10
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70
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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
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Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
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HCV prevalence and genotype distribution
Hajarizadeh B, Grebely J, Dore GJ. Nat Rev Gastroenterol Hepatol 2013
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Series10
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50
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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
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Key attributes of perfectovir
• Extremely high efficacy (>95%)
• Minimal toxicity
• Once daily dosing
• Pangenotypic
• Short duration (4-6 weeks)
HCV therapeutic development
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0
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50
60
70
80
90
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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
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0
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40
50
60
70
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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
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0
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60
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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
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0
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12 wks FDC (n=20)
SVR 12 %
Genotype 1, treatment naïve, F0-3
Kohli A et al, AASLD 2013
Sofosbuvir/Ledipasvir/3rdDAA
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0
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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
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HCV regimen approval timelines: Australia
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2020
PEG + RBV
20162014 20182015 20192017
PEG + RBV + TPV/BCP
HCV regimen approval timelines: Australia
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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
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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
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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
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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