DPC 083
ATAC Meeting
Seattle
February 24, 2002
Nancy Ruiz, MD
DPC 083-201 A Phase II Double-Blind (DB)
Comparison of 3 Once Daily Doses of the
NNRTI DPC 083 vs 600 mg Efavirenz (EFV)
in Combination with 2 NRTIs in HIV AntiRetroviral (ARV Treatment-Naïve Patients
Dr. Nancy Ruiz
R.Nusrat, A.Lazzarin, K.Arasteh, F.D.Goebel, S.Audgnotto,
A. Rachlis, J.R. Arribas, L.Ploughman, W. Fiske,
D.Labriola, R.Levy, R.Echols for the DPc 083-201 study team.
Limitations of Current NNRTIs
• Single Point Mutations Confer Resistance
– Efavirenz - K103N
– Nevirapine - Y181C, K103N
– (Delavirdine - not used - inferior efficacy)
• Inability to sequence NNRTIs
– Patients failing nevirapine with Y181C cannot be
successfully rescued with efavirenz
• Toxicities
– Efavirenz: CNS effects, primate teratogenicity, rash
– Nevirapine: rash, hypersensitivity, hepatotoxicity
DPC 083-201
Goals for a second generation NNRTI
• Coverage of pan-class resistance mutations
– Target K103N and viruses with multiple mutations
– Maintain potency against wild-type virus
• Safety and tolerability no worse than efavirenz
– Optimally reduce CNS and psychiatric side effects of
efavirenz
• Maintain long-half life allowing once daily dosing with
forgiveness for occasionally missed doses
DPC 083-201
Design of Second Generation NNRTIs
F3C
F3C
Cl
Cl
N
H
Efavirenz
Benzoxazinone
*BMS-561390
NH
O
O
N
H
O
DPC 083*
Quinazolinone
DPC 083-201
DPC 083* as a Second Generation NNRTI
• Potency
– towards “wild-type” HIV-1 essentially identical to
efavirenz
– towards mutant HIV-1 is 2 to 11-fold better
• Free fraction (protein binding)
– Free fraction is 5.3-fold higher than efavirenz
• Overall improvement (“Plasma IC90”) is >10-fold relative
to efavirenz
*BMS-561390
DPC 083-201
Study DPC 083-201 - Cohort 1 Design
ARV Naïve
Double-Blind
DPC 083* 50 mg once daily + Combivir bid
N=30
DPC 083* 100 mg once daily + Combivir bid
N=30
DPC 083* 200 mg once daily + Combivir bid
N=30
Efavirenz 600 mg once daily + Combivir bid
N=30
Safety, PK analysis and dose selection at 8 weeks
*BMS-561390
DPC 083-201
Study DPC 083-201 Objectives
• Compare the tolerability of the regimens
– 8 weeks considered adequate to assess potential CNS
effects and rash
• Determine PK in HIV-1-infected patients
• Determine mutations arising in failures (if any)
• Select phase III dose based on tolerability and PK.
• Dose selection not to be based on efficacy which was
expected to be comparable across doses
*BMS-561390
DPC 083-201
Study DPC 083-201
Demographics
Males
Median Age
Cauc
Black
Hisp.
*BMS-561390
85%
35 yr
83%
8%
5%
Study DPC 083-201
Baseline Characteristics
*BMS-561390
Mean Log 10 Plasma IV-RNA
4.52
Mean CD4
402
Study 201- On-Treatment Response Rates
D PC 0 8 3 -2 0 1 *
F ig u re 2 . 1
Pe rce n t a g e o f S u b je c ts w it h H I V - R N A < 5 0 C o p ie s /m L
O bs e rv e d
1 00
90
80
F
H
J
B
F
70
J
H
60
B
J
H
B
F
50
40
30
20
10
JH
F
B
0
0
2
B
H
F
J
4
6
8
10
12
14
16
18
W eeks
50m g
100m
200m
EFV
B
gJ
gH
F
*BMS-561390
N =
N=
N=
N=
27
29
37
35
27
28
33
35
26
25
32
32
26
26
32
31
25
26
31
31
DPC 083-201
Study 201 ITT (NC=F) Response Rates
DPC083-201*
Figure 2.2
Percentage of Subjects with HIV-RNA< 50 Copies/mL
Noncompleter = Failure
100
90
80
F
70
H
F
60
H
50
H
40
F
30
20
10
H
F
0
0
2
F
H
4
6
8
10
12
14
16
18
Weeks
50mg B N=
100mg J N=
200mg H N=
EFV F N=
*BMS-561390
29
30
38
37
29
30
38
37
29
30
38
37
29
30
38
37
29
30
38
37
DPC 083-201
Most Common Adverse Experiences
AE
DPC 083*
50 mg
N=26
%
DPC 083*
100 mg
N=25
%
DPC 083*
200 mg
N=35
%
efavirenz
600 mg
N=33
%
Rash
Nausea
Headache
Fatigue
Diarrhea
Dizziness
Abnormal
Dreams
15
27
12
19
11
8
12
36
24
20
16
4
4
0
51
29
20
14
17
14
3
33
33
9
12
6
30
3
DC due to AEs
8
12
20
15
*BMS-561390
DPC 083-201
Frequency of Specific CNS and
Psychiatric AEs
AE
DPC 083*
50 mg
N=26
%
DPC 083*
100 mg
N=25
%
DPC 083*
200 mg
N=35
%
efavirenz
600 mg
N=33
%
Dizziness
8
4
14
30
Insomnia
8
4
9
0
Abnormal
Dreams
Depression
12
0
3
3
8
8
6
6
Anxiety
4
0
3
3
Confusion
0
0
6
0
Suicidal
behavior
Aggression
0
4
0
3
8
0
3
3
1% of Patients discontinued for CNS or Psychiatric Adverse Experiences
*BMS-561390
DPC 083-201
Further Details on Rash
Characteristic
Urticaria %
Grade 1
(mild) %
Grade 2
(moderate) %
Grade 3
(severe) %
Grade 4
(maximal) %
Discontinue
for Rash %
Median Days
Duration
*BMS-561390
DPC 083*
50 mg
N=26
4
DPC 083*
100 mg
N= 25
4
DPC 083*
200 mg
N= 35
20
efavirenz
600 mg
N=33
12
0
8
11
9
12
20
26
15
4
8
14
9
0
0
0
0
4
8
14
9
11 days
13 days
9 days
13 days
DPC 083-201
Study DPC 083-201 Conclusions
• All DPC 083* doses adequately tolerated
• Tolerability equal or better than efavirenz except for rash at
the 200 mg dose
• No significant laboratory abnormalities (data not shown)
• All doses highly effective
• 100 mg dose selected for Phase III for NNRTI naïve
patients
• Potential benefit in reducing the frequency and severity of
rash with prophylactic use of a non-sedating antihistamine
will be explored in a 64 patient extension to Study 201
(cohort II)
*BMS-561390
DPC 083-201
Acknowledgements
Stephen Kravcik, MD
Anita Rachlis, MD
Stephen Shafran, MD
Chris Tsoukas, MD
Sharon Walmsley, MD
Stefan Esser, MD
Keikawus Arasteh, MD
Prof. Guido Gerken
Frank-Detlef Goebel, MD
Thomas Harrer, MD
Martin Hartmann, MD
Franz A. Mosthaf, MD
Juergen Rockstroh, MD
Gerd Faetkenheuer, MD
Prof. Reinhold E. Schmidt
Schlomo Staszewski, MD
Albert Theisen, MD
Philippa Easterbrook, MD
Mark Nelson, MD
Margaret Johnson, MD
Prof. Giampiero Carosi
Giovanni Di Perri, MD
Andrea Antinori, MD
Prof. Adriano Lazzarin
Prof. Fredy Suter
Prof. Fernando Aiuti
Prof. Francesco Chiodo, MD
Prof. L. Minoli
José Ramón Arribas, MD
Juan Gonzalez-Lahoz, MD
Esteban Ribera, MD
Refael Rubio, MD
Lutwin Weitner, MD
Prof. Gaetano Filice
DPC 083-203 A Phase II Comparison of
100 and 200 mg Once-Daily DPC 083 and 2
NRTIs in Patients Failing a NNRTI Containing
Regimen
Dr. Nancy Ruiz
R. Nusrat, E. Lauenroth-Mai, D. Berger, C. Walworth,
L.T. Bacheler, L. Ploughman, P.Tsang, D.Labriola, R. Echols,
R. Levy and the DPC 083-203 study team.
Unmet Medical Need
•Growing number of these people are treated with ARV drugs
•Growing prevalence of viral mutations resistant to available ARV
drugs seen in both treatment-experienced and -naïve patients
•Shift in proportion of patients given first-line therapy to secondline therapy and beyond
•Evolving practice of sequencing ARV drugs to maintain therapeutic
options in treatment-experience patients
•Increasing demand for second-generation ARV drugs that are
effective in suppressing mutant viral strains and provide simple
regimens that facilitate adherence
DPC 083-203
Future Goals of HIV Therapy
Efficacy
Quality of Life
•Wild-type virus
•Viral sanctuaries
•Mutant virus
•Tolerability
•Dosing interval
•Pill burden
Sustained HIV Suppression
•Durable therapy
•Long-term patient survival
•‘HIV is a manageable disease’
DPC 083-203
Plasma IC90 of DPC 083*
• Single Mutants
Value > 20,000 nM
8000
Plasma IC90, nM
7000
PLASMA IC90 DPC 083*
PLASMA IC90 EFAVIRENZ
6000
5000
4000
3000
2000
1000
0
L100I
*BMS-561390
K101E K103N
V106A
V108I
E138K
Y181C
Y188C
G190S
P225H
DPC 083-203
Plasma IC90 of DPC 083*
• Double mutants
Plasma IC90 DPC 083*
Plasma IC90 Efavirenz
*BMS-561390
K103N+L100I
G190S
Y188L
K103N+K101E
K103N+Y181C
1000
K103N+P225H
10000
K013N+V108I
Plasma IC90, nM
100000
DPC 083-203
Study DPC 083-203*
NNRTI-experienced, PI-naive
Double-blind
100 mg DPC 083* + 2 NRTIs
(N=75)
200 mg DPC 083* + 2 NRTIs
(N=75)
FDA had prohibited 200 mg dose until after August 16 meeting
Split into two studies, Non-IND study in Europe randomized patients
*BMS-561390
DPC 083-203
Study DPC 083-203*
Inclusion Criteria
NNRTI experienced, virologic failure
PI Naïve
Screening Genotyping while on NNRTI
*BMS-561390
Study DPC 083-203*
Demographics
Males
Median age
Cauc.
Black
Hisp.
*BMS-561390
93%
37yr
77%
16%
3%
Study DPC 083-203*
Baseline Characteristics
*BMS-561390
Mean Log 10 Plasma HIV-RNA
3.84
Mean CD4
518
Prior ARV Medications
100mg DPC 083*
200 mg DPC 083*
+ ZDV / 3 TC
+ ZDV / 3 TC
_____________________________________________________________________________________________
No. of Subjects
23
8
No. of Subjects who received medication
23 (100)
8 (100)
_____________________________________________________________________________________________
Nevirapine
15 (65.2)
5 (62.5)
Lamivudine
12 (62.5)
7 (87.5)
Stavudine
15 (65.2)
4 (50.0)
Efavirenz
8 (34.8)
4 (50.0)
Zidovudine
7 (30.4)
4 (50.0)
Lamivudine \ Zidovudine
7 (30.4)
1 (12.5)
Indinavir Sulfate
6 (21.7)
0 ( 0.0)
Didanosine
4 (17.4)
0 ( 0.0)
Ritonavir
4 (17.4)
0 ( 0.0)
Abacavir
2 ( 8.7)
1 (12.5)
Dideoxycytidine
3 (13.0)
0 ( 0.0)
Saquinavir Mesylate
1 ( 4.3)
1 (12.5)
Delavirdine Mesylate
1 ( 4.3)
0 ( 0.0)
Nelfinavir
1 ( 4.3)
0 (0.0)
Unknown Invest Agent (NOS) *
1 ( 4.3)
0 ( 0.0)
_____________________________________________________________________________________________
* Uknown Agent = Emtricibine / Placebo
*BMS-561390
Study DPC 083-203*
Number of New NRTIs at Baseline
None
One
Two
*BMS-561390
10
17
15
Premature Discontinuation
100mg DPC 083*
200 mg DPC 083*
+ZDV / 3TC
+ZDV / 3TC
TOTAL
_____________________________________________________________________________________________
No. of Subjects
23
8
31
No. of Subjects who prematurely
9 (39.13)
3 (37.50)
12 (30.71)
discontinued
_____________________________________________________________________________________________
Reason for Premature Discontinuation:
Adverse Experience
4 (17.39)
1 (12.50)
5 (16.13)
Protocol Violation
13 (56)
1 ( 12)
14 ( 45)
Withdrew Consent
0 ( 0.00)
1 (12.50)
1 ( 3.23)
Failed to return / Lost to follow-up
1 ( 4.35)
0 ( 0.00)
1 ( 3.23)
Unsatisfactory Thereputic Response
1( 4.35)
0 ( 0.00)
1 ( 3.23)
Other
1 ( 4.35)
0 ( 0.00)
1 ( 3.23)
Unknown
0 ( 0.00)
1 (12.50)
1 ( 3.23)
_____________________________________________________________________________________________
*BMS-561390
On-Treatment Response Rate in Study
DPC 083-203* Number of New NRTIs
# New NRTIs in
Regimen
% < 400 copies at
week 8
% < 400 copies at
last observation
No new NRTIs
1 New NRTIs
2 New NRTIs
4/10 (40%)
13/18 (72.2%)
10/15 (66.7%)
5/10 (50%)
10/18 (55.6%)
10/15 (66.7%)
• Includes only patients with data at week 8 or beyond and known choice of NRTIs
• Dose of DPC 083 remains blinded from patients not included in original analyses
• Maximum duration of treatment = 36 weeks
*BMS-561390
DPC 083-203
DPC083-203*
Percentage of Subjects with HIV-RNA < 400 Copies/mL
(Observed Data)
J
100
90
J
80
J
B
J
B
B
J
70
J
B
J
B
B
60
B
B
50
40
30
20
10
0
2
4
6*
8
12
16
20
24
WEEKS
B 100mg
N=
21
17
J 200mg
N=
7
8
11
12
13
11
10
5
7
6
5
5
4
* U.S. Patients Only
*BMS-561390
DPC 083-203
Percentage of Subjects with HIV-RNA < 50 Copies/mL
(Observed Data)
DPC083-203*
80
J
J
70
J
60
J
B
50
J
40
B
B
B
B
30
J
J
B
20
B
10
B
0
2
4
6*
8
12
16
20
24
WEEKS
B 100 MG
N=
21
17
J 200 MG
N=
7
8
11
12
13
11
10
5
7
6
5
5
4
* U.S. Patients Only
*BMS-561390
DPC 083-203
DPC083-203*
Percentage of Subjects with HIV-RNA < 400 Copies/mL
Non-Completer = Failure
J
100
90
80
J
70
J
B
60
J
B
50
B
J
B
B
40
B
30
20
10
0
2
4
6*
8
12
16
21
20
19
8
8
8
WEEKS
B 100mg
N=
23
23
J
N=
8
8
200mg
13
* U.S. Patients Only
*BMS-561390
DPC 083-203
Percentage of Subjects with HIV-RNA < 50 Copies/mL
DPC083-203*
Non-Completer = Failure
100
90
80
70
J
60
50
40
J
J
B
30
J
J
20
B
B
B
6
*
8
12
21
20
19
8
8
8
B
10
B
0
2
4
16
WEEKS
B
100mg
N=
23
23
J
200mg
N=
8
8
13
* U.S. Patients Only
*BMS-561390
DPC 083-203
Adverse Experiences
100mg DPC 083*
200 mg DPC 083*
+ZDV / 3TC
+ZDV / 3TC
_____________________________________________________________________________________________
ADVERSE EVENTS
_____________________________________________________________________________________________
Nervous System Disorder
Headache NOS
Insomnia NEC
Dizziness (Exc Vertigo)
Hypoaesthesia
Somnolence
Tremor NEC
6 (27.3)
3 (13.6)
3 (13.6)
1 ( 4.5)
1 ( 4.5)
0 ( 0.0)
0 ( 0.0)
4 (50.0)
2 (25.0)
0 ( 0.0)
0 ( 0.0)
0 ( 0.0)
1 (12.5)
1 (12.5)
Psychiatric Disorders
5 (22.7)
1 (12.5)
Abnormal Dreams
5 (22.7)
0 ( 0.0)
Anxiety NEC
2 ( 9.1)
0 ( 0.0)
Depressed Mood
0 ( 0.0)
1 (12.5)
Depression NEC
1 ( 4.5)
0 ( 0.0)
_____________________________________________________________________________________________
*BMS-561390
Summary of Rash Events
100mg DPC 083*
Number of subjects
Number of subjects with rash
Number of rashes
22
6 (27.3%)
6
Maximum Intensity
Mild
Moderate
1
5
Action Taken
None
Study Drug Discontinued
4
2
*BMS-561390
200mg DPC 083*
8
0
Summary of Rash Events
100mg DPC 083*
Onset of First Symptoms (days)
Median
Min, Max
13.5
9,77
Duration (days**)
Median
Min, Max
11
5,96
Impact on Lifestyle
None
Mild
Moderate
*BMS-561390
**Kaplan Meier estimates
2
1
3
Issues With DPC 083-203 Study
1)
2)
3)
4)
5)
6)
7)
*BMS-561390
Heterogeneous patient population
Poor recruitment
29% Premature discontinuations
Protocol violations eg. Prior PI
No clear dose response
Tolerability profile not well defined
No control arm
Conclusions
1) DPC 083 (BMS-561390) appears to be well tolerated in most
NNRTI experienced patients
2) Dose selection for NNRTI experienced patients not possible
from this study.
-Insufficient number of patients
-Heterogeneous patient population
-Insufficient data
3) Future Phase II study to determine tolerable and effective dose
in NNRTI patients in planning.
Acknowledgements
Daniel S. Berger, MD
Prof. Pierre Dellamonica
Dr. Pere Domingo
Prof. Christine Katlama
Keikawus Arasteh, MD
Martin Hartmann, MD
Franz A. Mosthaf, MD
Albrecht Stoehr, MD
Prof. Reinhold E. Schmidt
Prof. Willy W. Rozenbaum
Elke Lauenroth-Mai, MD
Santiago Moreno, MD
David Baker, MD
Hernando J. Knobel, MD
David A. Cooper, MD
Dr. Antonio Ocampo
Eliot W. Godofsky, MD
Prof. Francois Raffi
Mark T. Bloch, MD
Antonio Rivero, MD
Charles Farthing, MD
Jonathan Anderson, MD
Daniel Seekins, MD
Norm Roth, MD
David Dalmau, MD
Lutwin Weitner, MD
Dr. Jean-Michel Molina
Dr. Juergen Rockstroh
Schlomo Staszewski, MD
Prof. Jean-Francois Bergmann