DPC 083 ATAC Meeting Seattle February 24, 2002

DPC 083ATAC Meeting

SeattleFebruary 24, 2002Nancy 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 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



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

Demographics

Study DPC 083-201

Males 85%Median Age 35 yrCauc 83%Black 8%Hisp. 5%

*BMS-561390

Study DPC 083-201

Baseline Characteristics

Mean Log 10 Plasma IV-RNA 4.52

Mean CD4 402

*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

Demographics

Males 93%Median age 37yrCauc. 77%Black 16%Hisp. 3%

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

Number of New NRTIs at Baseline

None 10One 17Two 15

Study DPC 083-203*

*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

*


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


Non-Completer = Failure

WEEKS

*


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


Non-Completer = Failure

WEEKS*


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

DPC 083 ATAC Meeting Seattle February 24, 2002

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