Recent HCV treatment developments: In pursuit of perfectovir

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

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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

Key attributes of perfectovir

• Extremely high efficacy (>95%)

• Minimal toxicity

• Once daily dosing

• Pangenotypic

• Short duration (4-6 weeks)






• Pangenotypic



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





• Pangenotypic



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





• Pangenotypic



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 %




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 %




0

10

20

30

40

50

60

70

80

90

100

12 wks FDC (n=20)

SVR 12 %


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


HCV regimen approval timelines: Australia

2020

PEG + RBV

20162014 20182015 20192017

PEG + RBV + TPV/BCP


2020

PEG + RBV

20162014 20182015 20192017

PEG + RBV + TPV/BCP

PEG + RBV + Sofosbuvir / Simeprevir (G1)PBACTGA

IFN-free: Sofosbuvir + Ribavirin (G2/3)PBACTGA


2020

PEG + RBV

20162014 20182015 20192017

PEG + RBV + TPV/BCP



IFN-free: ABT450/r + Ombitasvir + Dasabuvir +/- Ribavirin (G1)

IFN-free: Sofosbuvir + Ledipasvir (G1)TGA PBAC

TGA PBAC


2020

PEG + RBV

20162014 20182015 20192017

PEG + RBV + TPV/BCP



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


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


Documents

Recent HCV treatment developments: In pursuit of perfectovir