NM283 - IHL Press

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NM283 - IHL Press
Progress with the clinical development of
valopicitabine (NM283) in combination
with peg-interferon for the treatment of
chronic hepatitis C, in treatment-naïve
patients and in non-responders to
peg-interferon/ ribavirin
Christopher O'Brien
University of Miami, USA
Progress in the Clinical Development of
Valopicitabine (NM283) in Combination
with Peg-Interferon for the Treatment of
Chronic Hepatitis C, in Treatment-Naïve
Patients and in Non-Responders to
Peg-Interferon / Ribavirin
Christopher O’Brien, M.D.
Center for Liver Diseases
University of Miami
Hep DART
Kohala Coast, Hawaii
December 2005
Potential Targets of Hepatitis C
Therapies
capsid
C
envelope
E1
NS3 Protease
domain
E2
protease/helicase
p7
NS2
NS3 Helicase
domain
NS3
NS4A
polymerase
NS4B
NS3 Bifunctional
protease / helicase
NS5A
NS5B
NS5B RNA-dependent
RNA polymerase
© 2002 JG McHutchison, DUMC
Valopicitabine
z
NM107
– Ribonucleoside
– NS5b polymerase inhibitor
– NM107-triphosphate
competitively inhibits viral
polymerase and is
incorporated into viral RNA,
causing chain termination
z
NM283
NH2
NH
O
N
HO
O
CH3
Val-O
OH
– Valyl ester pro-drug provides
Valopicitabine (NM283)
high oral bioavailability
2’-C-methylcytidine-3’-O-L-valine ester
– Plasma half life (4-6 hrs) &
intracellular half life (15 hrs)
support once daily dosing
NM107 is Active
in a Surrogate Virus Model and
Synergistic in Combination with IFN-α
8
No Drug
IFN 200 units/mL
6
BVDV Titer
Log10
Units/mL
NM107 8µM
4
2
0
IFN 200 units/mL + NM107 8 µM
0
2
4
6
8
10
12
Days
Cell-Based Persistent BVDV Infection Model
Valopicitabine: Clinical Trial Plan
Phase I
Phase II
ƒƒ Dose
Dose Escalation
Escalation
(001)
(001)**
ƒƒ NM283
α PK
NM283 /IFN
/IFNα
PK (003)*
(003)*
Treatment
Treatment Naives
Naives
ƒƒ Food
Food Effect
Effect (002)
(002)**
ƒƒ Phase
-1
Phase IIb
IIb HCV
HCV-1
Treatment
Treatment Failures
Failures
(004)*
(004)*
ƒƒ
ƒƒ
ƒƒ
Hepatic
Hepatic Impairment
Impairment
Renal
Renal Impairment
Impairment
Pharmaco
-interaction
Pharmaco-interaction
((Tacrolimus,
Tacrolimus, RBN,
RBN,
Cyclosporin
Cyclosporin))
ƒƒ Phase
-1
Phase IIb
IIb in
in HCV
HCV-1
Treatment
ïves
Treatment Na
Naïves
(006)*
(006)*
*Complete or ongoing
Phase III
ƒƒ Previous
Previous Treatment
Treatment
Failures
-1)
Failures (esp.
(esp. HCV
HCV-1)
ƒƒ Treatment
ïve (esp.
Treatment Na
Naïve
(esp.
HCV
-1)
HCV-1)
Final Phase I/II Trial Results for NM283: A
New Antiviral for Hepatitis C: Antiviral
Efficacy and Tolerance in Patients with
HCV-1 Infection
N Afdhal, E Godofsky, J Dienstag, V Rustgi,
L Shick, L Duncan, X-J Zhou, G Chao, C Fang,
B Fielman, M Myers, and N Brown
AASLD 2004
Boston, Massachusetts
Valopicitabine Phase I/II Trial (001):
Study Overview
z
First-in-Man dose escalation trial
z
Objectives: safety, antiviral activity, and PK
during 15-day treatment and 2 week posttreatment follow-up
z
95 adult patients with chronic hepatitis C enrolled
–
–
–
HCV genotype 1, ~90% IFNα failures
Serum HCV RNA ≥ 5 log10 IU/mL, ALT <5 x ULN
Compensated liver disease, no cirrhosis
z
Dosing levels: 50 – 800 mg per day
z
Each dosing cohort of 12 eligible patients
randomized 10:2 to NM283 vs. placebo
Presented by N Afdhal, AASLD 2004
Valopicitabine Phase I/II Trial (001):
Steady State (Day 15) NM107 PK after
Valopicitabine Dosing
Mean (SD) Single-Dose
Plasma Profiles of NM107
10000
100000
NM107
Plasma
Conc. 1000
Single-Dose NM107
AUC vs Dose
NM107
AUC0-inf
(ng/mL×hr)
(ng/mL)
10000
100
10
50 mg
100 mg
200 mg
400 mg
800 mg
0
4
8
12
Hours
16
20
24
1000
100
1000
NM283 Dose (mg/day)
ƒ Overall plasma exposure increases linearly with dose
ƒ Mostly comparable single-dose and steady-state PK
Presented by N Afdhal, AASLD 2004
Valopicitabine Phase I/II Trial (001):
Inhibition of HCV-1 Replication in
Patients
0.2
0
Serum
HCV RNA
Mean
Log10
Change
From
Baseline
Placebo
-0.2
50 mg QD
100 mg QD
-0.4
200 mg QD
400 mg QD
-0.6
200 mg BID
-0.8
Dose Titration
100-800 mg
-1
Dose Titration
400-800 mg +
antiemetic
800 mg QD
-1.2
Treatment Period
1 2 3 4 5
8
11
Study Day
15 16 17
22
Presented by N Afdhal, AASLD 2004
Valopicitabine Phase I/II Trial (001):
Safety & Tolerance
z
Clinical safety satisfactory overall
z
GI side effects in some patients
– Typically transient nausea
– Less frequent vomiting
z
No grade 3 or 4 lab abnormalities during
treatment
z
No pattern of lab abnormalities
Presented by N Afdhal, AASLD 2004
Valopicitabine (NM283) Alone And In
Combination With Peg-Interferon In Patients
With Genotype 1 Chronic Hepatitis C:
Preliminary Results From An Ongoing
Phase IIa (003), Multicenter Study
M Rodriguez-Torres, E Lawitz, E
Godofsky, N Afdhal, G Chao, B
Fielman Constance, S Knox,
and N Brown
DDW Annual Meeting
May 17, 2005 Chicago
Valopicitabine Phase IIa Trial (003):
Study Design
z
Safety, antiviral activity, & pharmacokinetics of NM283 vs.
NM283 + peg-IFNα-2b
z
Open-label design:
–
–
–
30 treatment-naïve adults with HCV-1 compensated CHC
HCV RNA >5 log10 IU/mL, ALT <5 times ULN
Eligible patients randomized 2:3 to:
• Valopicitabine (dose escalation to 800 mg/day; n=12) vs.
• Valopicitabine + peg-IFNα-2b (1.0 µg/kg QW; n=18)
z
Initial design called for 28 days’ treatment; encouraging early
data led to treatment extension to 48 weeks
z
Extension provides exploratory longer-term efficacy and
safety data for combination of Valopicitabine + peg-IFN
z
Study is ongoing to one year
Presented by M Rodriguez-Torres, DDW 2005
Valopicitabine Phase IIa Trial (003):
Patient Disposition
30 patients enrolled; EVR assessed at Wk 12
Valopicitabine
MonoRx (n=12)
Valopicitabine + Peg-IFNα
ComboRx (n=18)
11 Patients
1 Patient
6 Patients
12 Patients
No EVR (9) or
discontinued (2)
EVR
No EVR (3) or
discontinued (3)
On therapy
at Week 24
↓
↓
↓
Treatment stopped
at / before Week 12
↓
Treatment
continued
to Week 24
Treatment stopped 9 Pts completed
at / before Week 12
Week 24
Presented by M Rodriguez-Torres, DDW 2005
Valopicitabine Phase IIa Trial (003):
Treatment-Naïve Patients Serum HCV
RNA Levels, Baseline to Week 24
7
6
-1.9 log10 IU/mL
5
NM283 monoRx
(n=1/12)
Mean
Serum
4
HCV RNA
(Log10 IU/mL)
3
-3.58 log10 IU/mL
2
NM283 + Peg-IFNα-2b
ITT (n=9/18)
Amplicor LLOD = 50 IU/mL
1
0
0
2
4
6
8
10 12 14 16 18 20 22 24
Study Week
Adapted from Rodriguez-Torres, et al. DDW 2005
Valopicitabine Phase IIa Trial (003):
Individual HCV RNA Plots
All 9 ComboRx Patients Completing Week 24
At Week 24: 8 of 9 Patients <LLOQ Amplicor (600 IU/mL)
8
7 of 9 Patients <LLOD Amplicor (50 IU/mL)
7
6 of 9 Patients <LLOD TaqMan (10 IU/mL)
6
Serum
HCV RNA 5
(Log10 4
IU/mL)
3
Poor
Response
2
Late
responses
1
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Study Week
Presented by M Rodriguez-Torres, DDW 2005
Valopicitabine Phase IIa Trial (003):
Safety and Tolerance
z
Clinical safety satisfactory overall
z
No serious adverse events or dose-limiting
toxicities
z
Typical IFN side effects – no unexpected side
effects
z
Nausea/vomiting common in both Rx groups,
typically transient, probably related to both
Valopicitabine and IFN
z
One lab grade abnormality observed during
treatment: ANC ↓ (620/mm3) at Day 11 in a patient
receiving combination therapy
Presented by M Rodriguez-Torres, DDW 2005
Randomized Trial of Valopicitabine (NM283)
Alone and in Combination with Peg-Interferon
vs. Retreatment with Peg-Interferon plus
Ribavirin (PegIFN/RBV) in Hepatitis C Patients
with Previous Non-Response to PegIFN / RBV:
First Interim Results
C. O’Brien, E. Godofsky, M. Rodriguez-Torres,
N. Afdhal, S. Pappas, P. Pockros, E. Lawitz,
N. Bzowej, V. Rustgi, M. Sulkowski, K. Sherman,
I. Jacobson, G. Chao, S. Knox, K. Pietropaolo,
and N. Brown
AASLD 2005 Annual Meeting
San Francisco, CA
Nov. 14, 2005
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Key Inclusion Criteria
z
18-65 years of age, male or female
z
HCV genotype 1
z
Non-responders defined as adequate treatment course
–
–
–
–
z
Patients must have previously failed for efficacy, not tolerability
At least 12 weeks of pegIFN alfa + RBV
At least 75% of the prescribed doses of pegIFN and ribavirin
Failed to clear HCV RNA to non-detectable levels (relapsers
excluded)
Baseline
– HCV RNA > 105 IU/mL
– ALT ≤ 5 x ULN
z
Compensated liver disease
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Study Design
z
Multicenter (22), randomized, active control design
z
171 patients to be randomized in a 1:2:2:2:2 ratio
z
HCV RNA response criteria at Weeks 4, 12, 24
– Patients required to have HCV RNA drop ≥ 0.5 log at Week 4,
≥ 1.0 log at Week 12, and > 2.0 log at Week 24 to continue
treatment
– Early termination if viral response criteria not met
z
Primary efficacy endpoint: ITT analysis will be the SVR 6
months after the last dose of study medicine
– HCV RNA: COBAS TaqMan™ PCR assay (10 IU/mL; Roche)
– NM283 dosing groups pooled and compared to PegIFN +
ribavirin
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Treatment Arms
Valopicitabine (NM283) 800 monotherapy
Arm A
Valopicitabine (NM283)
400 monotherapy
Valopicitabine (NM283) 400
+ PEG-2a 180 µg
Valopicitabine (NM283)
400-800 monotherapy
Valopicitabine (NM283) 800
+ PEG-2a 180 µg
Valopicitabine (NM283)
800 monotherapy
Valopicitabine (NM283) 800 mg
+ PEG-2a 180 µg
Arm B
Arm C
Arm D
PEG IFN α-2a + RBV 1000-1200 mg/daily (75 kg cutoff)
Arm E
0
1
4
12
24
48
72
Weeks
n = 171
HCV RNA
Follow-up
Endpoints
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Demographics
800 mg
monoRx
NM283 Arms
400 mg
400-800
+
mg
PegIFN
+ PegIFN
800 mg
+
PegIFN
PegIFN +
Ribavirin
Number (n=190)
21
42
42
42
43
Gender (% Male)
81
67
67
71
61
Age (mean years)
51
51
50
52
51
Race: Caucasian (%)
71
76
69
64
51
Asian (%)
19
10
14
21
23
Mid-East/Indian (%)
10
14
14
12
23
Other (%)
0
0
2
2
2
Mean HCV RNA (log10
IU/mL)
6.9
6.9
7.0
7.0
6.9
No prior EVR (%)
81
81
81
81
81
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Current Status
z
190 patients were randomized (fully enrolled)
– 12 patients withdrew prior to receiving study
medications
• 9 withdrew consent after randomization to Peg-IFN/RBV
• 3 withdrew consent for other reasons
z
178 patients received study medications
– 21 patients discontinued by week 12
•
•
•
z
5 withdrew consent for other reasons
9 virologic non-response at week 4
7 discontinued for adverse events
157 patients reached week 12
– Trial is ongoing
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
HCV RNA Responses at Week 12
p = 0.01
80%
67%
70%
Patients
In
Category
(%)
PegIFN + RBV (ARM E)
p = 0.03
60%
50%
800 mg Valopicitabine + PegIFN
(combined ARM C + ARM D)
41%
41%
p = 0.05
40%
21%
30%
21%
20%
6%
10%
0%
>2 log
>3 log
>4 log
Log10 HCV RNA Suppression from Baseline
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004) Partial Data:
Mean Reduction HCV RNA at Week 24
Change from Baseline HCV
RNA (log 10)
0
Preliminary data: ITT Analysis
A 0.60 log
-0.5
-1
-1.5
-2
E 2.31 log
B 2.49 log
-2.5
C 3.01 log*
D 3.32 log*
-3
-3.5
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Study Week
A
NM283 800 mg QD
B
NM283 400 mg QD + Peg-IFN 180 µg QW
C
NM283 400-800 mg QD ramp (1st week) → 800 mg QD + Peg-IFN 180 µg QW
D
NM283 800 mg QD + Peg-IFN 180 µg QW
E
Ribavirin QD + Peg-IFN 180 µg QW
* p = .001 vs. RBV + PegIFN
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004) Partial Data:
HCV RNA Nondetectable Rate at Wk 24
z
HCV RNA is PCR-negative in:
– 0% of Arm A (NM383 monoRx)
– 18% of Arm B (NM23 400 + pegIFN)
– 11% of Arm C (NM283 400-800 + pegIFN)
– 25% of Arm D (NM283 800 +pegIFN)
– 19% of Arm E (PegIFN/RBV)
z
Median HCV RNA reduction at week 24
– Less (1.21 log10) in control arm (E) than in
NM283+pegIFN arms B-D (2.31, 3.01, and 3.29 log10,
respectively)
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Safety
z
Only 4% (n=7) discontinuations for adverse events
by week 12
z
Serious adverse events (SAE) in 6/178 patients (3%)
through week 12
– Two attributed to study medication (anemia,
dehydration)
– All SAEs have resolved
z
Laboratory abnormalities
– No hematologic toxicities (grade 1-4) for NM283
monotherapy; neutropenia and thrombocytopenia
in all arms with pegIFN
– Sporadic elevations of amylase, lipase, AST, ALT
occurred, these were mild (grade 1 & 2)
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Conclusions
z
Proportionally greater antiviral efficacy for
NM283 + pegIFN vs. pegIFN + RBV, in NonResponders
– Statistically superior antiviral efficacy (↓ HCV RNA
and EVR rate) for 2 higher NM283 + pegIFN doses
z
Overall safety / tolerance satisfactory to date
z
No viral breakthrough or resistance detected
to date
z
Continued decline in HCV RNA levels in the
two higher NM283 dosing groups encouraging
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Acknowledgments
Valopicitabine 004 Trial Clinical Investigators
z
z
Nezam Afdhal
z
z
Natalie Bzowej
z
Gary Davis
z
Michael Fried
z
Eliot Godofsky
z
z
Paul Kwo
z
Eric Lawitz
z
z
Karen Lindsay
USC School of Medicine, Los Angeles, CA
z
John McHutchison
z
z
z
z
Mark Sulkowski
Myron Tong
Huntington Memorial Hospital, Pasadena, CA
John Vierling
Baylor College School of Medicine
Idenix Pharmaceuticals, Inc., Cambridge, MA
Nathaniel Brown
George Chao
Keith Pietropaolo
Coleman Smith
Johns Hopkins Univ. School of Medicine, Baltimore, MD
Duke Clinical Research Institute, Durham, NC
z
z
z
Mitchell Shiffman
Minnesota Clinical Research, Saint Paul, MN
Alamo Medical Research, San Antonio, TX
z
z
McGuire VA Medical Center, Richmond, VA
Indiana University Medical Center, Indianapolis, IN
z
Lawton Shick
Univ. Massachusetts Medical School, Worcester, MA
Ira Jacobson
Weill Medical College of Cornell University, New York, NY
z
Kenneth Sherman
Univ. Cincinnati College of Medicine, Cincinnati, OH
Stuart Gordon
Henry Ford Health System, Detroit, MI
z
Vinod Rustgi
Metropolitan Research, Fairfax, VA
Bach & Godofsky, Bradenton, FL
z
Maribel RodriguezRodriguez-Torres
Fundacion de Invest. de Diego, Santurce, PR
UNC School of Medicine, Chapel Hill, NC
z
Paul Pockros
Scripps Clinic, La Jolla, CA
Baylor University Medical Center, Houston, TX
z
S. Chris Pappas
St. Luke's Episcopal Hospital, Katy, TX
Sutter Health, San Francisco, CA
z
Christopher O’Brien
Univ. Miami Center for Liver Diseases, Miami, FL
Beth IsraelIsrael-Deaconess Liver Center, Boston, MA
Barbara FielmanFielman-Constance
Steven Knox
Richard Boehme
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Resistance Monitoring
z
Preclinical results: BVDV surrogate virus and replicon
– NM283 resistance mutation may be S282T substitution in HCV
Pol 1
– BVDV mutants with the S282T homolog have reduced
sensitivity to NM283 but ~30-fold increased sensitivity to IFN1
z
Clinical results:
– No clear evidence of breakthrough in NM283 trials, with
treatment to 3 months in >150 patients and to 6 months in ~50
pts
– HCV RNA sequencing:
• No S282 mutants detected in 33 serum samples from 18 patients
(including poor responders) with treatment durations up to 169
days
• No mutations detected in domains B or C (S282 is domain B)
1 V.
Bichko et al. AASLD, 2005
Valopicitabine Phase IIa Trial (003):
Serum ALT Response to Week 24
70
65
60
Median
Serum
ALT
(IU/mL)
55
63% normal
at Week 24
↓
43% normal
at Week 12
↓
50
45
ULN (males)
40
35
ULN (females)
30
25
0
4
8
12
16
20
24
Study Week
Presented by M Rodriguez-Torres, DDW 2005
Valopicitabine (NM283) Phase IIb
Non-Responder Trial:
Categorical ALT Responses at Week 12
800 mg Valopicitabine + PegIFN
(combined ARM C + ARM D)
Mean
Serum
ALT
(Change
from
Baseline,
IU/L)
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
Mean Baseline ALT
77
PegIFN + RBV (ARM E)
Week 4
Week 8
87
Week 12
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
Most Frequent Adverse Events to Week 12
% of Patients With Event, Regardless of Relation to Study Drug
800 mg
Total with AE (%)
Nausea
Vomiting
Fatigue
Diarrhea
Headache
Insomnia
Decreased appetite
Myalgias
Neutropenia
Depression
Pyrexia
Arthralgias
Influenza-like illness
Rigors
(n=21)
400 mg
+ PegIFN
(n=41)
400-800
+ PegIFN
(n=41)
800 mg
+ PegIFN
(n=41)
RBV
+ PegIFN
(n=34)
(n=178)
95
67
48
10
33
10
0
24
0
0
14
10
5
0
5
100
68
49
44
32
37
5
12
27
17
5
17
10
5
12
100
78
51
46
54
34
24
15
15
22
20
10
15
20
10
100
78
78
59
27
27
20
22
17
24
15
17
22
22
15
100
32
6
56
15
24
32
15
18
12
27
15
12
15
15
99
66
48
46
33
28
17
17
17
17
16
14
14
14
12
Includes adverse events occurring in at least 10% of patients overall
Total
Valopicitabine Phase I/II Trial (001):
Conclusions
z
Consistent, dose-related antiviral activity in
HCV-1 infected patients, primarily (87%)
previous interferon failures
– Mean HCV RNA reductions 0.15 – 1.21 log10
IU/mL at doses of 50 to 800 mg/day
– Individual patient range (800 mg/day cohort)
0.41 – 2.37 log10 IU/mL
z
Satisfactory safety – no dose-limiting
toxicities, some transient nausea &
vomiting, all compliant patients (78/79)
completed treatment
Presented by N Afdhal, AASLD 2004
Valopicitabine Phase IIa Trial (003):
Conclusions
z
Marked antiviral activity for valopicitabine + peg-IFNα
z
For 9 ComboRx patients completing Week 24:
– Mean HCV RNA ↓ 4.5 log10 IU/mL (range: -2.33 to -6.2 log10)
– Continuing ‘late’ HCV RNA reductions:
• 4 of 5 pts with detectable HCV RNA at Week 12 had multi-log
drops after Week 12
• Results suggest kinetics of response to Valopicitabine + PegIFNα may differ from kinetics of response to peg-IFNα + ribavirin
z
No HCV RNA “breakthroughs” to date, with data to 24 weeks
– Viral genotyping (HCV Pol) underway
z
Good Tolerability
– Negligible hematologic side effects – possible safety
advantage
Presented by M Rodriguez-Torres, DDW 2005
Valopicitabine (NM283) Phase IIb
Non-Responder Trial (004):
EVR Results Week 12
Treatment Group
n
Mean ↓ HCV RNA
Pts with EVR†
(log10 IU/mL)
Number (%)
A NM283 monoRx
21
0.78
1 (5%)
B NM283 400 + pegIFN
41
2.22
24 (54%)
C NM283 400-800 + pegIFN
41
2.51 *
29 (71%) *
D NM283 800 + pegIFN
41
2.77 *
26 (63%) *
E PegIFN + RBV retreatment
34
1.92
14 (41%)
* p < 0.001 vs pegIFN + RBV (comparisons of C and D to E)
† EVR
= early virologic response: ≥ 2 log10 (99%) drop in serum HCV RNA
Christopher O’Brien, M.D.
Center for Liver Diseases
University of Miami School of Medicine
z
I have the following financial arrangements to disclose:
– Grants/research support
• Idenix Pharmaceuticals, Coley Pharmaceuticals, Valeant
Pharmaceuticals, Hoffmann-La Roche Inc, Vertex
Pharmaceuticals, Schering-Plough, IDUN Pharmaceuticals / Pfizer
Inc, InterMune, Inc, GlaxoSmithKline Inc, Ortho Biotech, Otsuka
Pharmaceutical Co., Ltd
– Consultant
• Schering-Plough
– Speakers Bureau
• Bristol-Myers Squibb, Axcan Pharma Inc, Schering-Plough,
Gilead Sciences, Hoffmann-La Roche Inc
z
My presentation includes the investigational use for treatment
of chronic hepatitis C:
– Valopicitibine as monotherapy
– And in combination with PegIFN alfa-2a