Session Viral Hepatitis B & D: Clinical Saturday April 25, 2015 - - PowerPoint PPT Presentation

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Session Viral Hepatitis B & D: Clinical Saturday April 25, 2015 - - PowerPoint PPT Presentation

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Session Viral Hepatitis B & D: Clinical Saturday April 25, 2015 Cihan Yurdaydin, MD 1 2 Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis Cihan Yurdaydin, Ramazan

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Session Viral Hepatitis B & D: Clinical Saturday April 25, 2015 Cihan Yurdaydin, MD

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Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis

Cihan Yurdaydin, Ramazan Idilman, Ingrid Choong, Cagdas Kalkan, Onur Keskin, M Fatih Karakaya, E Ali Tuzun, Ersin Karatayli, Mithat Bozdayi, David Cory, Jeffrey S Glenn

3 ¡

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Hepatitis D Virus

  • HDV is always associated with HBV Infection
  • HDV worldwide prevalence is 15 million
  • HDV is the most severe form of viral hepatitis
  • More rapid progression to liver cirrhosis and liver cancer
  • No FDA approved Rx for HDV
  • In absence of an approved therapy, HDV screening is limited

4 ¡

HBsAg

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Classic Antivirals Ineffective Against HDV

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  • IFN-α effective in ~ 25% of chronic HDV patients
  • HBV nucleos(t)ide analogs (NAs) are ineffective
  • IFN-α + NAs (HIDIT 1 / HIDIT 2) no better than IFN
  • No direct acting agents have been studied for HDV

¡

5 ¡ Yurdaydin et al, Sem Liver Dis 2013

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Prenylation is Key to HDV Life Cycle

Farnesyl Transferase Inhibitors Target Prenylation

Ciancio et al; Nature Reviews Gastroenterology & Hepatology 11, 68–71 (2014)

Entry ¡ Inhibitors ¡ e.g. ¡Farnesyl ¡ transferase ¡inhibitors ¡

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SLIDE 7

Prenylation Inhibitors as Antivirals

Compelling Preclinical Rationale

Proof of Concept Virus Like Particle (VLP) Infectious Virus In-Vivo Animal Model

l Jeffrey S. Glenn

7 ¡

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SLIDE 8

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  • Small molecule, oral, inhibitor of farnesyl transferase
  • Inhibits farnesylation of large delta antigen
  • Blocks assembly and packing of viral particles
  • High theoretical barrier to resistance
  • Phase 2a POC in HDV infected patients completed
  • NIH study presented at 2014 AASLD (Boston)

Lonafarnib

Well-Characterized Clinical Stage Lead Compound

8 ¡ N O N O NH2 N Br Br Cl

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SLIDE 9

9 ¡ LNF 100 mg BID LNF 200 mg BID

100 80 60 40 20

% Patients Achieving ≥ 1 Log VL Decline

100% 33%

PEG IFN-α 2a* versus Lonafarnib in HDV

% Patients Achieving ≥ 1 Log Decline in HDV-RNA

NIH NIH

Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #1860.

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SLIDE 10

10 ¡ LNF 100 mg BID PEG IFN α 2a 180 mcg QW + Tenofovir QD LNF 200 mg BID

100 80 60 40 20

% Patients Achieving ≥ 1 Log VL Decline

33% 68% 79% 100% 33%

PEG IFN-α 2a* versus Lonafarnib in HDV

% Patients Achieving ≥ 1 Log Decline in HDV-RNA

HIDIT - 2 NIH NIH

Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #1860.

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11 ¡ LNF 100 mg BID PEG IFN α 2a 180 mcg QW + Tenofovir QD LNF 200 mg BID

100 80 60 40 20

% Patients Achieving ≥ 1 Log VL Decline

33% 68% 79% 100% 33%

PEG IFN-α 2a* versus Lonafarnib in HDV

% Patients Achieving ≥ 1 Log Decline in HDV-RNA

HIDIT - 2 NIH NIH

?

Wöbse et al, AASLD 2014, # 1613; Koh et al, AASLD 2014, #1860.

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Aims of Study

Explore if efficacy can be optimized by:

  • increasing lonafarnib dose
  • increasing lonafarnib intake frequency
  • combination therapy with peg-interferon
  • combination therapy with ritonavir

12 ¡

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LOWR HDV – 1 Study

LOnafarnib With and without Ritonavir

Patients and Methods

  • Treatment duration 4 - 8 weeks
  • 72 hour PK and PD evaluation on day 1 and day 28
  • Testing frequency: days 1, 2, 3, 7, 14, 28 and then Q2W

– Biochemical parameters – HDV RNA (by in-house quantitative real-time PCR) – HBV DNA (by Cobas, Taqman, Amplicor)

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n=3 ¡

LOWR HDV – 1 Study

LOnafarnib With and without Ritonavir in HDV

n=3 ¡

Assess: Efficacy, Tolerability, PK, Viral Load

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n=3 ¡ n=3 ¡ n=3 ¡

Lonafarnib 200 mg BID Lonafarnib 300 mg BID Lonafarnib 100 mg TID Lonafarnib 100 mg BID + Ritonavir 100 mg QD Lonafarnib 100 mg BID + PEG IFN-α 180 mcg QW

Month ¡1 ¡

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15 ¡

Day 28 Reduction in Serum HDV RNA

Lonafarnib 100 mg BID + Ritonavir 100 mg QD

0.5

  • 0.5
  • 1
  • 1.5
  • 2
  • 2.5

Mean ∆

  • 2.2 Log

N = 3

Change in Log HDV RNA copies/mL

Mean ∆

  • 1.8 Log

Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

N = 3 N = 3

Lonafarnib 300 mg BID

Mean ∆

  • 2.0 Log

Lonafarnib 200 mg BID

Mean ∆

  • 1.6 Log

N = 3

LOWR-1

N = 3

Lonafarnib 100 mg TID

Mean ∆

  • 1.5 Log
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SLIDE 16

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Day 28 Reduction in Serum HDV RNA

Lonafarnib 100 mg BID Placebo Lonafarnib 100 mg BID + Ritonavir 100 mg QD

0.5

  • 0.5
  • 1
  • 1.5
  • 2
  • 2.5

Mean ∆

  • 0.74 Log

Mean ∆

  • 2.2 Log

Mean ∆

  • 0.2 Log

N = 4 N = 6 N = 3

Change in Log HDV RNA copies/mL

Mean ∆

  • 1.8 Log

Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

N = 3

Lonafarnib 200 mg BID

Mean ∆

  • 1.6 Log

N = 6 N = 3

Lonafarnib 300 mg BID

Mean ∆

  • 2.0 Log

Lonafarnib 200 mg BID

Mean ∆

  • 1.6 Log

N = 3

NIH (AASLD 2014) LOWR-1

N = 3

Lonafarnib 100 mg TID

Mean ∆

  • 1.5 Log
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SLIDE 17

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Day 28 Reduction in Serum HDV RNA

Lonafarnib 100 mg BID Placebo Lonafarnib 100 mg BID + Ritonavir 100 mg QD

0.5

  • 0.5
  • 1
  • 1.5
  • 2
  • 2.5

Mean ∆

  • 0.74 Log

Mean ∆

  • 2.2 Log

Mean ∆

  • 0.2 Log

N = 4 N = 6 N = 3

Change in Log HDV RNA copies/mL

Mean ∆

  • 1.8 Log

Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

N = 3

Lonafarnib 200 mg BID

Mean ∆

  • 1.6 Log

N = 6 N = 3

Lonafarnib 300 mg BID

Mean ∆

  • 2.0 Log

Lonafarnib 200 mg BID

Mean ∆

  • 1.6 Log

N = 3

NIH (AASLD 2014) LOWR-1

N = 3

Lonafarnib 100 mg TID

Mean ∆

  • 1.5 Log
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SLIDE 18

LOWR HDV – 1

LOnafarnib With and without Ritonavir

18 ¡ LNF ¡+ ¡RTN ¡ N=10 ¡

Month 1 N=3 Lonafarnib 100 mg BID + Ritonavir 100 mg QD

LNF ¡+ ¡RTN ¡ N=10 ¡

Month 2 Lonafarnib 100 mg BID + Ritonavir 100 mg QD Assessments: Safety, Tolerability, HDV-RNA, PK

LNF ¡+ ¡RTN ¡ N=10 ¡

N=3 Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

LNF ¡+ ¡RTN ¡ N=10 ¡

Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

Boost with Ritonavir Complement with PEG IFN

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  • ­‑6.0 ¡
  • ­‑5.0 ¡
  • ­‑4.0 ¡
  • ­‑3.0 ¡
  • ­‑2.0 ¡
  • ­‑1.0 ¡

0.0 ¡ 1.0 ¡ 0 ¡ 10 ¡ 20 ¡ 30 ¡ 40 ¡ 50 ¡ 60 ¡ 70 ¡ 80 ¡ PaBent ¡1 ¡ PaBent ¡2 ¡ PaBent ¡3 ¡

Viral Load Declines on Lonafarnib + Ritonavir

Week 4 Mean Change in HDV-RNA Viral Load -2.2 Log Week 8 Mean Change in HDV-RNA Viral Load -3.2 Log

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Change in Log HDV RNA copies/mL BLQ undetectable Lonafarnib 100 mg BID + Ritonavir 100 mg QD Post-treatment Days

BLQ = below limit of quantification

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SLIDE 20

0 ¡ 50 ¡ 100 ¡ 150 ¡ 200 ¡ 250 ¡ 300 ¡ 0 ¡ 2 ¡ 4 ¡ 6 ¡ 8 ¡ 10 ¡ 12 ¡

20 ¡

ALT U/L Lonafarnib 100 mg BID + Ritonavir 100 mg QD

Normalization of ALT on Lonafarnib + Ritonavir

ALT Levels Maintained After Treatment

Normal ¡ 10-­‑40 ¡U/L ¡

PaBent ¡1 ¡ PaBent ¡2 ¡ PaBent ¡3 ¡ Week Post-treatment

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SLIDE 21

Lonafarnib PK Boosted by Ritonavir

Serum Concentration Increased 4-5 Fold

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  • ­‑4.0 ¡
  • ­‑3.5 ¡
  • ­‑3.0 ¡
  • ­‑2.5 ¡
  • ­‑2.0 ¡
  • ­‑1.5 ¡
  • ­‑1.0 ¡
  • ­‑0.5 ¡

0.0 ¡ 0 ¡ 2 ¡ 4 ¡ 6 ¡ 8 ¡ 10 ¡ 12 ¡ PaBent ¡1 ¡ PaBent ¡2 ¡ PaBent ¡3 ¡

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Viral Load Declines on Lonafarnib + Peg IFN

Week 4 Mean Change -1.8 Log Week 8 Mean Change -3.0 Log

Post-treatment LNF 100 mg BID + PEG IFN 180 mcg QW Week Change in Log HDV RNA copies/mL

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23 ¡ 50 100 150 200 Day 1 Day 28 Day 35 Day 56 Day 84

ALT U/L Lonafarnib 100 mg BID + PEG IFN α 2a 180 mcg QW

Normal ¡ 10-­‑40 ¡U/L ¡

PaBent ¡1 ¡ PaBent ¡2 ¡ PaBent ¡3 ¡

ALT Improvement of Lonafarnib + PEG IFN

ALT Levels Continue to Decline After Treatment

Post Treatment Week 4 Week 5 Week 8 Week 12 Week 0

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SLIDE 24
  • 4.0
  • 3.5
  • 3.0
  • 2.5
  • 2.0
  • 1.5
  • 1.0
  • 0.5

0.0 2 4 6 8 10 12 Mean Viral Load Change ( Log Copies/mL) Week On-Treatment Post-treatment

Earlier VL Decline with Lonafarnib Combination

Lonafarnib Combinations Display Biphasic Kinetics and More Rapid Onset

LNF 100 mg BID + RTN 100 mg QD (N=3) LNF 100 mg BID + PEG IFN-α 2a 180 mcg QW (N=3) 24 ¡

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SLIDE 25
  • 4.0
  • 3.5
  • 3.0
  • 2.5
  • 2.0
  • 1.5
  • 1.0
  • 0.5

0.0 2 4 6 8 10 12 Mean Viral Load Change ( Log Copies/mL) Week On-Treatment Post-treatment

Earlier VL Decline with Lonafarnib Combination

Lonafarnib Combinations Display Biphasic Kinetics and More Rapid Onset

LNF 100 mg BID + RTN 100 mg QD (N=3) LNF 100 mg BID + PEG IFN-α 2a 180 mcg QW (N=3) HIDIT-2: PEG IFN 180 mcg QW ± tenofovir QD (N=91) 25 ¡

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  • ­‑3.5 ¡
  • ­‑3 ¡
  • ­‑2.5 ¡
  • ­‑2 ¡
  • ­‑1.5 ¡
  • ­‑1 ¡
  • ­‑0.5 ¡

0 ¡ 0 ¡ 5 ¡ 10 ¡ 15 ¡ 20 ¡ 25 ¡ 30 ¡ 35 ¡ 40 ¡ 45 ¡

LNF ¡100 ¡mg ¡BID ¡+ ¡PEG ¡IFN ¡180 ¡mcg ¡QW ¡ LNF ¡100 ¡mg ¡BID ¡+ ¡RTN ¡100 ¡mg ¡QD ¡

HIDIT-2: PEG IFN 180 mcg QW ± tenofovir QD (N=91)

Earlier VL Decline with Lonafarnib Combination

Lonafarnib Combinations Display Biphasic Kinetics and More Rapid Onset

Mean VL Change (Log IU/mL) Week (N=3) (N=3)

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Side effects Improved with LNF Combos

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  • Mainly GI side effects
  • Graded according to Common Terminology Criteria for

Adverse Events

  • Lonafarnib chronically dosed in Progeria for 2 years

(PNAS, 2012, 16666)

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SLIDE 28

Summary and Conclusions

  • LOWR – 1 Study: promising combos for further exploration
  • Lonafarnib + Ritonavir ≥ ¡3 log drop at Month 2
  • Lonafarnib + Pegasys ≥ 3 log drop at Month 2
  • LOWR – 2 Study: “Dose-Finding” study on-going
  • Exploring lonafarnib + ritonavir combinations for longer dosing
  • Lonafarnib is first oral therapy for HDV
  • More rapid onset than PEG-IFN
  • Host-targeting Rx with high barrier to resistance

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