DPC 083 ATAC Meeting Seattle February 24, 2002

1
DPC 083ATAC MeetingSeattleFebruary 24, 2002

• Nancy Ruiz, MD

2
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.
3
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
4
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
5
Design of Second Generation NNRTIs
Cl
Cl
NH
O
O
O
DPC 083 Quinazolinone
Efavirenz Benzoxazinone
DPC 083-201
BMS-561390
6
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 gt10-fold
  relative to efavirenz

DPC 083-201
BMS-561390
7
Study DPC 083-201 - Cohort 1 Design
ARV Naïve Double-Blind
DPC 083 50 mg once daily Combivir bid
N30
DPC 083 100 mg once daily Combivir bid
N30
DPC 083 200 mg once daily Combivir bid
N30
Efavirenz 600 mg once daily Combivir bid
N30
Safety, PK analysis and dose selection at 8 weeks
DPC 083-201
BMS-561390
8
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
9
Study DPC 083-201
Demographics
Males 85 Median Age 35 yr Cauc 83 Black
8 Hisp. 5
BMS-561390
10
Study DPC 083-201
Baseline Characteristics
Mean Log 10 Plasma IV-RNA 4.52 Mean CD4 402
BMS-561390
11
Study 201- On-Treatment Response Rates
DPC 083-201
BMS-561390
12
Study 201 ITT (NCF) Response Rates
DPC 083-201
BMS-561390
13
Most Common Adverse Experiences
DPC 083-201
BMS-561390
14
Frequency of Specific CNS and Psychiatric AEs
1 of Patients discontinued for CNS or
Psychiatric Adverse Experiences
DPC 083-201
BMS-561390
15
Further Details on Rash
DPC 083-201
BMS-561390
16
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
17
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
18
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.
19
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
20
Future Goals of HIV Therapy

• 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

DPC 083-203
21
Plasma IC90 of DPC 083

• Single Mutants

Value gt 20,000 nM
Plasma IC90, nM
DPC 083-203
BMS-561390
22
Plasma IC90 of DPC 083

• Double mutants

Plasma IC90, nM
DPC 083-203
BMS-561390
23
Study DPC 083-203
NNRTI-experienced, PI-naive Double-blind
(N75)
100 mg DPC 083 2 NRTIs
(N75)
200 mg DPC 083 2 NRTIs
FDA had prohibited 200 mg dose until after August
16 meeting Split into two studies, Non-IND study
in Europe randomized patients
DPC 083-203
BMS-561390
24
Study DPC 083-203
Inclusion Criteria
NNRTI experienced, virologic failure PI Naïve
Screening Genotyping while on NNRTI
BMS-561390
25
Study DPC 083-203
Demographics
Males 93 Median age 37yr Cauc. 77 Black 16
Hisp. 3
BMS-561390
26
Study DPC 083-203
Baseline Characteristics
Mean Log 10 Plasma HIV-RNA 3.84 Mean CD4 518
BMS-561390
27
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 1
2 (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) Dideoxycytidi
ne 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
28
Study DPC 083-203
Number of New NRTIs at Baseline
None 10 One 17 Two 15
BMS-561390
29
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
30
On-Treatment Response Rate in Study DPC 083-203
Number of New NRTIs

• 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
31
Percentage of Subjects with HIV-RNA lt 400
Copies/mL
DPC083-203
(Observed Data)
J
100
90
J
B
J
J
80
B
J
B
B
J
J
70
B
B
B
60
B
50
40
30
20
10
0

2
4
6
8
12
16
20
24
WEEKS
N
21
17
11
12
13
11
10
5
B
100mg

N
7
8
7
6
5
5
4
J
200mg

U.S. Patients Only
DPC 083-203
BMS-561390
32
Percentage of Subjects with HIV-RNA lt 50 Copies/mL
DPC083-203
(Observed Data)
80
J
J
70
J
J
60
B
B
J
50
B
40
B
B
30
J
B
J
20
B
10
B
0

2
4
6
8
12
16
20
24
WEEKS
B
N
21
17
11
12
13
11
10
5
100 MG

N
7
8
7
6
5
5
4
J
200 MG

U.S. Patients Only
BMS-561390
DPC 083-203
33
Percentage of Subjects with HIV-RNA lt 400
Copies/mL
DPC083-203
Non-Completer Failure
J
100
90
80
J
70
J
J
B
60
B
J
50
B
B
B
B
40
30
20
10
0

2
4
6
8
12
16
WEEKS
B
100mg
N
23
23
13
21
20
19

J
200mg
N
8
8
8
8
8

U.S. Patients Only
BMS-561390
DPC 083-203
34
Percentage of Subjects with HIV-RNA lt 50 Copies/mL
DPC083-203
Non-Completer Failure
100
90
80
70
J
60
50
40
J
J
B
30
B
J
J
B
B
20
B
10
B
0
2
4
6
8
12
16

WEEKS
B
100mg
N
23
23
13
21
20
19

J
200mg
N
8
8
8
8
8

U.S. Patients Only
DPC 083-203
BMS-561390
35
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
36
Summary of Rash Events
100mg DPC 083 200mg DPC 083
Number of subjects 22 8 Number of subjects
with rash 6 (27.3) 0 Number of rashes
6 Maximum Intensity Mild 1 Moderate
5 Action Taken None 4 Study Drug
Discontinued 2
BMS-561390
37
Summary of Rash Events
100mg DPC 083
Onset of First Symptoms (days) Median 13.5 Min
, Max 9,77 Duration (days) Median
11 Min, Max 5,96 Impact on Lifestyle None
2 Mild 1 Moderate 3
BMS-561390
Kaplan Meier estimates
38
Issues With DPC 083-203 Study
1) Heterogeneous patient population 2) Poor
recruitment 3) 29 Premature discontinuations 4)
Protocol violations eg. Prior PI 5) No clear
dose response 6) Tolerability profile not well
defined 7) No control arm
BMS-561390
39
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.
40
Acknowledgements
Santiago Moreno, MDHernando J. Knobel, MD Dr.
Antonio Ocampo Prof. Francois Raffi Antonio
Rivero, MD Jonathan Anderson, MD Norm Roth,
MD Lutwin Weitner, MD Dr. Juergen
Rockstroh Schlomo Staszewski, MD Prof.
Jean-Francois Bergmann
David Baker, MD David A. Cooper, MD Eliot W.
Godofsky, MD Mark T. Bloch, MD Charles Farthing,
MD Daniel Seekins, MD David Dalmau, MD Dr.
Jean-Michel Molina
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, MDProf. Reinhold E.
Schmidt Prof. Willy W. Rozenbaum Elke
Lauenroth-Mai, MD