dpc 083 atac meeting seattle february 24, 2002 nancy ruiz, md
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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 Anti-Retroviral (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 NNRTIsDesign of Second Generation NNRTIs
NH
NHCl
O
F3C
DPC 083*Quinazolinone
OCl
O
F3C
NH
EfavirenzBenzoxazinone
DPC 083-201*BMS-561390
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
DPC 083-201*BMS-561390
Study DPC 083-201 - Cohort 1 Design
ARV NaïveDouble-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
DPC 083-201*BMS-561390
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
DPC 083-201*BMS-561390
Study 201- On-Treatment Response Rates
B
B
B B
B
J J
J
J
J
H H
H
H
H
F F
F
F F
0
10
20
30
40
50
60
70 80
90
100
0 2 4 6 8 10 12 14 16 18
Figure 2.1 Percentage of Subjects with HIV -RNA < 50 Copies/mL
Observed
Weeks
DPC 083 -201*
N = 27 27 26 26 25 N= 29 28 25 26 26 N= 37 33 32 32 31 N= 35 35 32 31 31
50mg B
100mg J 200mg H
EFV F
DPC 083-201*BMS-561390
Study 201 ITT (NC=F) Response Rates
HH
H
H
H
FF
F
F
F
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18
Figure 2.2Percentage of Subjects with HIV-RNA < 50 Copies/mL
Noncompleter = Failure
Weeks
DPC 083-201*
N = 29 29 29 29 29 N= 30 30 30 30 30 N= 38 38 38 38 38 N= 37 37 37 37 37
50mgB100mgJ200mgHEFV F
DPC 083-201*BMS-561390
Most Common Adverse Experiences
AE DPC 083*50 mgN=26
DPC 083*100 mgN=25
DPC 083*200 mgN=35
efavirenz600 mgN=33
% % % %
Rash 15 36 51 33
Nausea 27 24 29 33
Headache 12 20 20 9
Fatigue 19 16 14 12
Diarrhea 11 4 17 6
Dizziness 8 4 14 30
AbnormalDreams
12 0 3 3
DC due to AEs 8 12 20 15
DPC 083-201*BMS-561390
Frequency of Specific CNS and Psychiatric AEs
AE DPC 083*50 mgN=26
DPC 083*100 mgN=25
DPC 083*200 mgN=35
efavirenz600 mgN=33
% % % %
Dizziness 8 4 14 30
Insomnia 8 4 9 0
AbnormalDreams
12 0 3 3
Depression 8 8 6 6
Anxiety 4 0 3 3
Confusion 0 0 6 0
Suicidalbehavior
0 4 0 3
Aggression 8 0 3 3
1% of Patients discontinued for CNS or Psychiatric Adverse Experiences
DPC 083-201*BMS-561390
Further Details on Rash
Characteristic DPC 083*50 mgN=26
DPC 083*100 mgN= 25
DPC 083*200 mgN= 35
efavirenz600 mgN=33
Urticaria % 4 4 20 12
Grade 1(mild) %
0 8 11 9
Grade 2(moderate) %
12 20 26 15
Grade 3(severe) %
4 8 14 9
Grade 4(maximal) %
0 0 0 0
Discontinuefor Rash %
4 8 14 9
Median DaysDuration
11 days 13 days 9 days 13 days
DPC 083-201*BMS-561390
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)
DPC 083-201*BMS-561390
Acknowledgements
Stephen Kravcik, MDAnita Rachlis, MDStephen Shafran, MDChris Tsoukas, MDSharon Walmsley, MDStefan Esser, MDKeikawus Arasteh, MDProf. Guido GerkenFrank-Detlef Goebel, MDThomas Harrer, MDMartin Hartmann, MDFranz A. Mosthaf, MD
Juergen Rockstroh, MDGerd Faetkenheuer, MDProf. Reinhold E. SchmidtSchlomo Staszewski, MDAlbert Theisen, MDPhilippa Easterbrook, MDMark Nelson, MDMargaret Johnson, MDProf. Giampiero CarosiGiovanni Di Perri, MDAndrea Antinori, MDProf. Adriano Lazzarin
Prof. Fredy SuterProf. Fernando AiutiProf. Francesco Chiodo, MDProf. L. MinoliJosé Ramón Arribas, MDJuan Gonzalez-Lahoz, MDEsteban Ribera, MDRefael Rubio, MDLutwin Weitner, MDProf. 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 second- line 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
DPC 083-203
Efficacy
•Wild-type virus•Viral sanctuaries•Mutant virus
Quality of Life
•Tolerability•Dosing interval•Pill burden
Sustained HIV Suppression
•Durable therapy•Long-term patient survival•‘HIV is a manageable disease’
Plasma IC90 of DPC 083*Plasma IC90 of DPC 083*
• Single Mutants
L100I K101EK103N V106A V108I E138K Y181C Y188C G190S P225H0
1000
2000
3000
4000
5000
6000
7000
8000
PLASMA IC90 DPC 083*PLASMA IC90 EFAVIRENZ
Pla
sma I
C9
0,
nM
Value > 20,000 nM
DPC 083-203*BMS-561390
Plasma IC90 of DPC 083*Plasma IC90 of DPC 083*
• Double mutantsK
013N
+V
108I
K103N
+P
225H
K103N
+Y
181C
K103N
+K
101E
Y188L
G190S
K103N
+L
100I
1000
10000
100000Plasma IC90 DPC 083*Plasma IC90 Efavirenz
Pla
sma I
C90,
nM
DPC 083-203*BMS-561390
Study DPC 083-203*
NNRTI-experienced, PI-naive
Double-blind
200 mg DPC 083* + 2 NRTIs
100 mg DPC 083* + 2 NRTIs
(N=75)
(N=75)
FDA had prohibited 200 mg dose until after August 16 meetingSplit into two studies, Non-IND study in Europe randomized patients
DPC 083-203*BMS-561390
Inclusion Criteria
NNRTI experienced, virologic failure
PI Naïve
Screening Genotyping while on NNRTI
Study DPC 083-203*
*BMS-561390
Baseline Characteristics
Mean Log 10 Plasma HIV-RNA 3.84
Mean CD4 518
Study DPC 083-203*
*BMS-561390
Prior ARV Medications100mg DPC 083* 200 mg DPC 083* + ZDV / 3 TC + ZDV / 3 TC
_____________________________________________________________________________________________No. of Subjects 23 8No. 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
Premature Discontinuation
100mg DPC 083* 200 mg DPC 083* +ZDV / 3TC +ZDV / 3TC TOTAL
_____________________________________________________________________________________________No. of Subjects 23 8 31No. 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 inRegimen
% < 400 copies atweek 8
% < 400 copies atlast observation
No new NRTIs 4/10 (40%) 5/10 (50%)1 New NRTIs 13/18 (72.2%) 10/18 (55.6%)2 New NRTIs 10/15 (66.7%) 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
DPC 083-203*BMS-561390
B
BB
BB
B
B
B
J
J
J
JJ J
J
2 4 6 8 12 16 20 240
10
20
30
40
50
60
70
80
90
100
N= 21 17 11 12 13 11 10 5
N= 7 8 7 6 5 5 4
Percentage of Subjects with HIV-RNA < 400 Copies/mL
(Observed Data)
WEEKS
*
* U.S. Patients Only
B
100mg
J
200mg
DPC083-203*
DPC 083-203*BMS-561390
B
B
B
B
B
B
B
B
JJ
J
J
J J
J
2 4 6 8 12 16 20 240
10
20
30
40
50
60
70
80
N= 21 17 11 12 13 11 10 5
N= 7 8 7 6 5 5 4
Percentage of Subjects with HIV-RNA < 50 Copies/mL(Observed Data)
WEEKS
*
* U.S. Patients Only
DPC083-203*
B 100 MG
J 200 MG
DPC 083-203*BMS-561390
B
BB
B
B B
J
J
J J
J
2 4 6 8 12 160
10
20
30
40
50
60
70
80
90
100
N= 23 23 13 21 20 19
N= 8 8 8 8 8
Percentage of Subjects with HIV-RNA < 400 Copies/mL
Non-Completer = Failure
WEEKS
*
* U.S. Patients Only
B
100mg
J
200mg
DPC083-203*
DPC 083-203*BMS-561390
B
B
B B B
B
J J
J
J J
2 4 6 8 12 160
10
20
30
40
50
60
70
80
90
100
N= 23 23 13 21 20 19
N= 8 8 8 8 8
Percentage of Subjects with HIV-RNA < 50 Copies/mL
Non-Completer = Failure
WEEKS*
* U.S. Patients Only
B
100mg
J
200mg
DPC083-203*
DPC 083-203*BMS-561390
Adverse Experiences
100mg DPC 083* 200 mg DPC 083* +ZDV / 3TC +ZDV / 3TC
_____________________________________________________________________________________________ADVERSE EVENTS_____________________________________________________________________________________________
Nervous System Disorder 6 (27.3) 4 (50.0)Headache NOS 3 (13.6) 2 (25.0)Insomnia NEC 3 (13.6) 0 ( 0.0)Dizziness (Exc Vertigo) 1 ( 4.5) 0 ( 0.0)Hypoaesthesia 1 ( 4.5) 0 ( 0.0)Somnolence 0 ( 0.0) 1 (12.5)Tremor NEC 0 ( 0.0) 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* 200mg DPC 083*
*BMS-561390
Number of subjects 22 8Number of subjects with rash 6 (27.3%) 0Number of rashes 6
Maximum IntensityMild 1Moderate 5
Action TakenNone 4Study Drug Discontinued 2
Summary of Rash Events
100mg DPC 083*
Onset of First Symptoms (days)Median 13.5Min, Max 9,77
Duration (days**)Median 11Min, Max 5,96
Impact on LifestyleNone 2Mild 1Moderate 3
*BMS-561390**Kaplan Meier estimates
Issues With DPC 083-203 Study
1) Heterogeneous patient population2) Poor recruitment3) 29% Premature discontinuations4) Protocol violations eg. Prior PI5) No clear dose response 6) Tolerability profile not well defined 7) No control arm
*BMS-561390
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, MDProf. Pierre DellamonicaDr. Pere DomingoProf. Christine KatlamaKeikawus Arasteh, MDMartin Hartmann, MDFranz A. Mosthaf, MDAlbrecht Stoehr, MDProf. Reinhold E. SchmidtProf. Willy W. RozenbaumElke Lauenroth-Mai, MD
Santiago Moreno, MDHernando J. Knobel, MDDr. Antonio OcampoProf. Francois RaffiAntonio Rivero, MDJonathan Anderson, MDNorm Roth, MDLutwin Weitner, MDDr. Juergen RockstrohSchlomo Staszewski, MDProf. Jean-Francois Bergmann
David Baker, MDDavid A. Cooper, MDEliot W. Godofsky, MDMark T. Bloch, MDCharles Farthing, MDDaniel Seekins, MDDavid Dalmau, MDDr. Jean-Michel Molina
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