issues for drug development in special...

Issues for Drug Development in

Special Populations

Raymond T Chung, MD

Director of Hepatology and Vice Chief, GI

Mass. General Hospital

Boston, MA

Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA

Welcome to the revolution, but…..

• PEG/RBV/TLP or BOC are the new SOC

• However, they will not benefit all in need

• Issues

– Efficacy

– Tolerability

• Drug specific AEs

• Dependence on IFN +/- RBV backbone

– Resistance

– Drug-drug interactions


HCV and special populations

HCV-HIV coinfection

Post-liver transplant

Renal failure

Cirrhotics/decompensated

IFN contraindicated or intolerant

Nonresponders to Peg/RBV/PI

African Americans and Hispanics


Natural History of HCV

Exposure

(Acute phase)

Resolved Chronic

Cirrhosis Stable or

variably progressive

Slowly

Progressive HCC

Transplant

Death

20% (16)

20% (20) 80% (80)

25% (4)

80% (64)

75% (12)

25 yrs 20 yrs Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA

Natural History of HCV: HIV as

accelerant

Exposure

(Acute phase)

Resolved Chronic

Cirrhosis Stable or

variably progressive

Slowly

Progressive HCC

Transplant

Death

20% (16)

20% (20) 80% (80)

25% (4)

80% (64)

75% (12)

15 yrs 10 yrs

HIV


Issues in the management of HIV

coinfection

• Higher HCV RNA levels

– Increased potential for resistance

– Role for PEG/RBV leadin?

• Need for longer durations of Rx

• Greater medication burden – ART

interactions and potential for intolerability

• Adherence concerns


Telaprevir: Drug drug interactions with ART

• TPV and BOC 3A4 inhibitor and substrate

• Interactions difficult to predict

• AUC of telaprevir reduced by HIV PIs (particularly

lopinavir)

• Modest DDI between TVR and ATV/r, no dose

adjustment deemed necessary1

• TDF: no dose adjustment was deemed necessary1

• TPV not recommended with LPV, fosAMP, DRV

• EFV decreases TVR AUC, higher TVR dose (1125

mg q8h) mostly offsets reduced exposures to TVR

with EFV1

• No significant interactions with raltegravir anticipated

1Van Heesink et al. CROI 2011; Abstract 146LB


Boceprevir and ART

• Ritonavir (CYP 3A4 inhibitor) did not substantively affect exposure to BOC

• No dosage adjustment is needed for the

coadministration of BOC with tenofovir

• DDI with other agents not reported

• ↓mean BOC trough concentration when coadministered

with efavirenz will be clearer as data from coinfected

populations are obtained

Casserra C et al. CROI 2011


TPV + P/R in HCV-HIV: Study 110 Design

Part A: no ART

24 0 48 72 Weeks 12 36

Follow-up PR48

(control) PR

SVR Pbo + PR

T/PR TVR + PR Follow-up SVR

PR

Follow-up PR48

(control) PR

SVR Pbo + PR

T/PR TVR + PR Follow-up SVR

PR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

Sulkowski et al. CROI 2011


Principal Eligibility Criteria

• Male and female patients, 18 to 65 years of age with chronic HCV

genotype 1/HIV-1 co-infection, and treatment-naïve for HCV

• Liver biopsy within 1 year; compensated cirrhosis permitted

• Part A: up to 20 patients not receiving ART, with CD4 count

≥500 cells/mm3, and HIV RNA ≤100,000 copies/mL

• Part B: up to 48 patients receiving a stable ART regimen

–TDF/EFV/FTC, or

–ATV/r with TDF and FTC or 3TC, with CD4 count ≥300 cells/mm3,

and HIV RNA ≤50 copies/mL


Undetectable HCV RNA at Week 4 (ITT)

5/7 12/16 9/14 0/8 1/8 0/6

71 75

0

64

12

0

Perc

en

t o

f p

ati

en

ts w

ith

HC

V R

NA

Un

dete

cta

ble

Telaprevir + PR

n/N =

PR

0

10

20

30

40

50

60

70

80

90

100

No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC

PR

70

26/37 1/22

5

Total

Total



Undetectable HCV RNA at Week 12 (ITT)

5/7 12/16 8/14 1/8 1/8 1/6

71 75

17

57

12 12

Perc

en

t o

f p

ati

en

ts w

ith

HC

V R

NA

Un

dete

cta

ble

Telaprevir + PR

n/N =

PR

0

10

20

30

40

50

60

70

80

90

100

No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC

PR

68

14

3/22 25/37

Total

Total



HCV Virological Failure

• 2 telaprevir patients experienced viral breakthrough*:

– 1 patient at week 4 (receiving ATV/r + TDF + FTC)

– 1 patient at week 8 (receiving EFV/TDF/FTC)

• 4 patients discontinued treatment due to stopping rules:

– 1 telaprevir patient (receiving EFV/TDF/FTC) at week 8

– 3 placebo patients

• HCV sequencing has not been performed yet

*defined as HCV RNA >100 IU/mL after HCV RNA undetectable or a 1 log10 increase from nadir

Sulkowski et al. CROI 2011 Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA

Median Telaprevir Trough Plasma Concentrations

were Similar with and without ART

EFV/TDF/FTC (n=6-11)

ATV/r + TDF + FTC/3TC (n=6-8)

No ART (n=5-6)

2 4 6 8 10 12

1000

2000

3000

4000

0

Weeks

0

Tela

pre

vir

Tro

ug

h P

las

ma

Co

ncen

trati

on

s (

ng

/mL

)


Change from Baseline in Median ART Trough

Plasma Concentrations after T/PR Initiation

Time (Weeks)

Tenofovir (n=14-19)

Efavirenz (n=9-12)

Atazanavir (n=5-6)

Ch

an

ge f

rom

Baselin

e (

%)

0 2 4 6 8 10 12

0

20

40

60

80

-20

-40

< 20% median change from

baseline concentration


Cyclophilin Antagonists

• Cyclophilin A essential cofactor for HCV, HIV replication

– CyA aids incorporation of NS5B into HCV replication complex

– Also assists HIV replication

• CsA inhibits CyA, blocks HCV and HIV in culture

models[2]

• CsA also inhibits calcineurin immunosuppression[1]

• Nonimmunosuppressive cyclophilin antagonists

– Alisporivir (-3.6 log w/monotherapy in HCV/HIV)[3]

– SCY635 (-2.3 log w/monotherapy in HCV)[4]

– high barrier to resistance

– broadly active across genotypes

– Phase 2 studies underway

1. Liu Z, et al. J Virol. 2009;83:6554-6565. 2. Watashi K, et al. Hepatology. 2003;38:1282-1288. 3. Flisiak R, et al. Hepatology. 2008;47:817-826. 4. Hopkins S, et al. EASL 2010. Abstract 34.


Efficacy of Alisporivir in HIV/HCV-Coinfected

Patients

• DEBIO-025: oral small

molecule inhibitor of

cyclophilin

• 1200 mg twice daily for

14 days (n = 16) vs placebo

(n = 3) in treatment-naive

HIV/HCV-coinfected

patients

• Effective across GT 1, 3, 4

• No rebounds noted

• Modest HIV antiviral effect

also noted (-1log10)

Flisiak R et al. Hepatology 2008;47:817.

1

2

3

4

5

6

7

8

9

-28 0 10 20 30 40 50

Time (Days)

DEBIO-025 Placebo

HC

V R

NA

(lo

g10 c

op

ies/m

L)

Treatment


HCV-HIV: Drug development

considerations • Encouraging on-treatment responses thus far

• ART DDIs do not appear to interfere with PI

success

• Circumscribed duration of HCV treatment will be

advantageous

• Behavior of RAVs over long-term unknown

• Cyclophilin antagonists will be of potential

interest in refractory patients



HCV-HIV coinfection


Renal failure






Post-LT HCV

• HCV most important and frequent cause of

post-LT graft failure, mortality

• Accelerated natural history post-LT

• Limited PEG/RBV response rates (~20%)

• High rates of PEG, RBV intolerability



OLT is associated with a 16-fold rise

in HCV load (n = 75)

1

10

100

1000

10000

100000

1000000

10000000

Hep

ati

tis C

vir

al R

NA

levels

(x 1

00

0 e

qu

iva

len

ts p

er

mL

)

Pre-transplant Post-transplant

Chazouilleres, Gastro, 1994

p<.0001


Dynamics of HCV viremia following

OLT (n = 25)

100

1000

10000

100000

pre-OLT 1wk 1mth 2mth 3mth 6mth 12mth

OLT

Time after OLT

HC

V R

NA

(K

eq

/ml)

Gane, Gastro, 1996

Major issues in post-LT HCV in

DAA era

• Drug drug interactions of HCV PIs with CNIs

– TPV increases AUC of Tac by 70x, CsA by 4.6x

– Unknown interaction with SRL but likely as well

– Not approved for use in post-LT

– BOC DDIs have not yet been completed

• No optimal primary I/S identifiable

– Antibody based Rx (Thymo, anti-IL2R)

– Attempt dosing of CNIs by levels?

– Should treatment of HCV wait until later post-LT when

ACR less pressing an issue?

Garg V et al. Hepatology 2011, in press


Dose-Normalized CsA Exposure Increased

4.6-Fold After Multiple TVR Doses

• Mean CsA T1/2 increased from 12 h to 42 h

• Dose-Normalized Cmax increased by 1.3-fold

0 10 20 30 40 50 60 70 80 90 1000.01

0.1

10

1

Cyclosporine A

Cyclosporine A + Telaprevir (day 1)

Cyclosporine A + Telaprevir (day 8)

Cyc

losp

ori

ne M

ea

n B

loo

d C

on

cen

tra

tio

n(n

g/m

L/m

g)

Do

se N

orm

alized

Nominal Time (h)



Dose-Normalized Tac Exposure Increased

70-Fold After Multiple TVR Doses

• Mean Tac T1/2 increased from 41 h to 196 h

• Dose-Normalized Cmax increased 9.4-fold

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 1501

10

100

1000

10000

100000 Tacrolimus

Tacrolimus + Telaprevir (day 8)

Ta

cro

lim

us

Me

an

Blo

od

Co

nc

en

tra

tio

n(p

g/m

L/m

g)

Do

se N

orm

alize

d

Nominal Time (h)



Alternative approaches to management of

post-LT HCV

• Other Rx classes

– Nuc polymerase inhibitors – high barrier to

resistance, limited DDI

– NS5A inhibitors

– Host cofactor inhibitors

• Preemptive Rx

– Treat prior to establishment of allograft infection

– Nadir of infection - lowest risk for RAV selection

– Couple DAAs with MAbs (Immunoprophylaxis +

antiviral prophylaxis)



HCV-HIV coinfection


Renal failure






Treatment of HCV in Renal Failure

• RBV is renally cleared, not dialyzed, and

contraindicated in those with profound renal

impairment

• TPV, BOC do not require dose adjustment

• PegIFN monotherapy is current SOC

– High rates of intolerability

– Poor SVR rates (35%)

• PEG + PI Rx

– Limited SVR rates in phase II studies

– High relapse rates


PROVE2: the indispensability of RBV

0

20

40

60

80

100

SV

R (

%)

48

36

62 68

PegIFN/RBV + Placebo

48w (n=82)

TPV 12w+ PegIFN

12w (n=78)

TPV 12w+ PegIFN/RBV 12w (n=82)

TPV 12w+ PegIFN/RBV 24w (n=81)

P = .08

P = .01

20 14 29 48 Relapse, %

P > .20

Hezode C et al, NEJM 2009;360:1839-50 Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA

Treatment Options in the Renally

Impaired Patient

• PEG + PI

• PEG + PI + Pol inhibitor (Nuc)

• PEG + PI + NS5A

• PEG + PI + host cofactor inhibitor

• All oral DAAs

• PEG as SOC



HCV-HIV coinfection


Renal failure






The cirrhotic and decompensated

patient

• Phase III trials of TPV and BOC

– Diminished SVR rates for compensated cirrhotics

– limited tissue penetration of PI vs. inherently limited

response in cirrhotics?

– 48 wks recommended for PEG/RBV + TPV or BOC

– Future trials may require cirrhosis stratification

• Decompensated cirrhosis

– Dependence on PEG precludes safe administration of

PEG/RBV/TPV or BOC

– All DAA regimen, or DAAs + HCI best option

– Unmet need, no SOC comparator


REALIZE: SVR by Baseline Fibrosis

Stage and Prior Response Prior

Relapsers

Prior Partial

Responders

Prior Null

Responders

Pooled T12/PR48

Pbo/PR48

SV

R (

%)

2/15 n/N= 53/62 144/167 12/38 0/5 10/18 34/47 3/17 0/9 15/38 11/32 1/5 2/15 48/57 24/59 1/18 7/50 1/10

No, minimal

or portal

fibrosis

Cirrhosis Stage

Bridging

fibrosis

No, minimal

or portal

fibrosis

Cirrhosis Bridging

fibrosis

No, minimal

or portal

fibrosis

Cirrhosis Bridging

fibrosis

Pockros P, et al. DDW 2011; Chicago, IL; May 7 -10, 2011; Abst. 625.



HCV-HIV coinfection


Renal failure





HCV in the IFN contraindicated or

intolerant

No options for those with absolute or relative C/Is except

for IFN sparing regimens (all DAAs or DAAs + HCIs)

– Alternative IFNs (PEG-IFNl1) may be an option if

principal toxicity was hematologic

The relatively intolerant patient may be offered

– a brief (≤ 4wk) IFN course + DAAs +/- HCIs

– Alternative IFNs with improved therapeutic index

An attractive population for trial design in view of no

options for the SOC group


Virologic response by IL28B Genotype:

Peg-l1/RBV vs Peg-α2a/RBV

Naïve Genotypes 1, 4 x 48 wks

0

n = 19 46 22 38 17 40 18 57 19 46 22 38 17 40 18 57

RVR cEVR

10

20

30

40

50

60

70

80

90

100

Hatched bars: CT/TT Solid bars: CC

120 μg 180 μg 240 μg PegIFN-λ

180 μg PegIFN-α-2a

120 μg 180 μg 240 μg PegIFN-λ

180 μg PegIFN-α-2a

Pe

rce

nta

ge o

f p

atie

nts

± 9

5%

CI

Zeuzem S, et al. EASL 2011. Abstract 1360. Presented at the 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy, 22-23 June 2011, Cambridge, USA

Changes in Hematologic Parameters Over Time

and PegIFN and RBV Dose Reductions

He

mo

glo

bin

(g/

L)

Pla

tele

ts (

GI/

L)

To

tal

Ne

utr

op

hils

(G

I/L)

LLN

Study Week

LLN

150

140

130

120

0 6 8 10 12 2 4

300

250

200

150

0 6 8 10 12 2 4

5 4

2 1

3

0 6 8 10 12 2 4

LLN

PegIFN-λ 120 µg PegIFN-λ 180 µg

PegIFN-λ 240 µg PegIFN-α-2a

PegIFN-λ

PegIFN

α-2a

Lab Toxicity, % 120 µg

(N=128)

180 µg

(N=131)

240 µg

(N=134)

180 µg

(N=133)

Hemoglobin low 20.5 15.4 12.9 43.9

RBV dose reduction, % (due to Hb abnormality)

2.3 1.5 0.7 12.8

Neutrophils Low 0 0.8 0 15.2

Platelets Low 0 0 0 1.5

PegIFN dose reduction, % (due to hematologic abnormality)

0 0 0 17.3

Zeuzem S, et al. EASL 2011. Abstract 1360.



HCV-HIV coinfection


Renal failure






PEG-RBV-PI nonresponders

The new unmet need

Expect numbers in this group to continue to grow

Options include:

Quad therapy trials given demonstration of proof of

concept

– PEG RBV + 2 DAAs or 1 DAA + 1 HCI

PEG RBV + 1 DAA from another class (including 2nd gen

PIs

All oral DAAs or DAAs + HCIs


Proof of concept: SVR with DAAs only

21 PEG/RBV null responders with gt 1 (< 2 log drop at

W12) randomized to 24 weeks of

– Arm A: BMS 790052 QD (NS5A inhibitor) + BMS 650032

BID (NS3 inhibitor)

– Arm B: Arm A + PEG/RBV (Quad therapy)

• Arm A: 4/11 SVR12, 6/11 patients had breakthrough with PEG/RBV added 4 achieved undetectable HCV RNA (treatment ongoing)

Arm B: 10/10 had SVR12

Hope for most recalcitrant populations with quad or all oral

DAAs

For PEG/RBV/PI failures, re-tx with PEG/RBV/PI as “SOC”

arm poses challenge Lok A, et al. EASL 2011. Abstract 1356.


Lok A, et al. EASL 2011. Abstract 1356.

PI + NS5A inhibitor ± PegIFN/RBV in prior null

responders

HC

V R

NA

(lo

g10 I

U/m

L)

HC

V R

NA

(lo

g10 I

U/m

L)

Group A: no pegIFN/RBV, n = 11

Group B: pegIFN/RBV, n = 10

PT, posttreatment.



HCV-HIV coinfection


Renal failure






HCV in African Americans and

Hispanics

• Addition of 1st generation PIs has narrowed the

gap between

– IL28B favorable and risk genotypes

– African-Americans and Caucasians

– Hispanics and Caucasians

• Anticipate less need for separate stratification

on ethnic variables


ADVANCE and ILLUMINATE: SVR Rates

60/99 599/804 62/89 15/38 151/333 7/28

61

75

25

70 73

44

Pe

rce

nt

of

pa

tie

nts

w

ith

SV

R

T12PR

n/N =

PR (control)

45 39

Black/African American Non-Black/African American

Hispanic/Latino Non-Hispanic/Latino

588/801 143/323

0

10

20

30

40

50

60

70

80

90

100

Flamm et al DDW – May 9, 2011


Conclusions

• Management of special populations will be next

major challenge post-approval of 1st generation

PIs

• Dependent on additional data re PK, clearance,

efficacy, DDIs, and tolerability in certain risk

groups

• Key will be well planned trials in these unmet

need populations

• SOC will be limited or nonviable

– Unmet need populations an attractive path to

approval for DAAs?


issues for drug development in special...

Documents