Efficacy and safety of lersivirine vs efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: Week 48 primary analysis results from an ongoing, multicenter, randomized, double-blind, Phase 2b trial (Study A5271015)

P Vernazza,1 C Wang,2 A Pozniak,3 E Weil,2 P Pulik,4 DA Cooper,5 R Kaplan,6 A Lazzarin,7 H Valdez,8 J Goodrich,9 C Craig,10 J Mori,10

M Tawadrous2

1Cantonal Hospital, St. Gallen, Switzerland; 2Pfizer Inc., Groton, CT, USA; 3Chelsea & Westminster Hospital, London, UK; 4Provincial Infectious Hospital of Warsaw, Warsaw, Poland; 5Kirby Institute, University of New South Wales, Sydney, Australia; 6Desmond Tutu HIV Foundation, Cape Town, South Africa; 7Universita Vita-Salute San Raffaele, Milan, Italy; 8Pfizer Inc., New York, NY, USA; 9ViiV Healthcare, Research Triangle Park, NC, USA; 10Pfizer Global Research & Development, Sandwich Laboratories, Kent, UK

6th IAS Conference, July 17-20, 2011, Rome, Italy

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Lersivirine: a next-generation NNRTI with unique binding and potent activity against HIV-1• Binds to the reverse transcriptase

(RT) enzyme in a novel way1

• Unique resistance profile2 • Antiretroviral (ARV) activity2

– IC50 = 5.83 nM; 1.81 ng/mL (PBC)• Resistance generated in vitro2

– V108I pathway to resistance• Synergy between lersivirine (LRV)

and NRTIs and integrase strand-transfer inhibitors2

Y181

Lersivirine

K103X-ray crystal structure of LRV bound at the non-nucleoside

binding site of recombinant HIV-1 RT

*PBC= protein binding corrected 1. Phillips C et al. 2007; 2. Corbau R et

al. 2010

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Phase 2b treatment-naïve trial design

• Randomized, double-blind, comparative study• Selection criteria

– ARV naïve– HIV-1 RNA ≥1000 c/mL– CD4+ >200 cells/mm3

– No RT mutations by standard genotyping• Stratified by viral load (<100,000 or ≥100,000 c/mL) & geographic region (A

& B)c/mL, copies per milliliter; LRV, lersivirine; QD, once daily; TDF/FTC: tenofovir disoproxil fumarate/emtricitabine

Randomization 1:1:1

EFV 600 mg QD + TDF/FTC

LRV 750 mg QD + TDF/FTC

0 48 wk 96 wk6 weeks 24 wk

Planned interimanalysis

Primary endpoint: Patients achieving HIV-1 RNA <50 c/mL

LRV 500 mg QD + TDF/FTC

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Statistical methods

Primary efficacy endpoint• Percentage of subjects with plasma HIV-1 RNA <50

c/mL at Week 48 (non-completer/missing=failure), ITT – Treatment differences estimated by Cochran-Mantel-

Haenszel adjusting for stratification factors– 2-sided 80% confidence interval

Secondary endpoints • Change from baseline CD4+ cell counts (LOCF, ITT)• Fasting change from baseline lipid endpoints

(observed values, completers)– ANCOVA including stratification factors and baseline

measurements as covariates– 2-sided 80% confidence interval

ITT, intent-to-treat; LOCF, last observation carried forward. ANCOVA= analysis of covariates

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AE, adverse event; “Others”= subjects no longer willing to participate in study, withdrawn due to pregnancy, relocation* Considered by Investigator to be at least possibly related to study drug

Patient disposition99

ineligible

63 randomized to EFV

63 treated

1 did not receive study drug

1 did not receive study drug

0 did not receive study drug

54 remaining in study at ≥48 weeks

12 Discontinuations

4 Insufficient clinical response 3 AE

- Vomiting*- Disturbance in

attention*- B-cell lymphoma 2 Lost to follow-up 3 Others

66 randomized to LRV 750 mg

65 treated

53 remaining in study at ≥48 weeks

66 randomized to LRV 500 mg

65 treated

53 remaining in study at ≥48

weeks

195 randomized

294 subjects screened

12 Discontinuations

5 Insufficient clinical response 3 AE

- Hypersensitivity*- ↑ ALT*- Leukocyturia* 1 Lost to follow-up 3 Others

9 Discontinuations 1 Insufficient clinical response 5 AE

- ↑ ALT, AST, amylase*- Psychotic disorder *- Abnormal dreams, mental

disorder, suicidal ideation *

- Anxiety*- Disturbance in attention*

0 Lost to follow-up 3 Others

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Demographic and baseline characteristics

LRV 500 mg

N=65

LRV 750 mg

N=65

EFV 600 mg

N=63Mean Age, years (range) 37 (24-61) 36 (22-62) 36 (21-61)Female, n (%) 16 (25) 19 (29) 17 (27)Race, n (%) White Black Other

40 (62)18 (28)7 (11)

38 (59)22 (34)

5 (8)

34 (54)24 (38)

5 (8)Region, n (%)

South AfricaOther

18 (28)47 (72)

22 (34)43 (66)

24 (38)39 (62)

HIV-1 subtype, n (%)BCOther

42 (65)17 (26)

6 (9)

40 (62)22 (34)

3 (5)

37 (59)22 (35)

4 (6)Screening plasma HIV-1 RNA (c/mL), n (%)

<100,000≥100,000

45 (69)20 (31)

44 (68)21 (32)

41 (65)22 (35)

Screening plasma HIV-1 RNA (log10 c/mL), median (range)

4.7 (3.3-5.8) 4.7 (3.2-6.8) 4.7 (3.4-6.0)

Screening CD4 cell count (cells/mm3), median (range)

320 (183-806)

323 (200-955)

317 (122-553)

Treated = 193

Randomized = 195

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0 2 4 8 16 24 32 40 480

102030405060708090

100

Time (weeks)

% o

f sub

ject

s with

pla

sma

HI

V-1

RNA

<50 c

/mL t

hrou

gh W

eek

48

LRV 500 mgLRV 750 mgEFV 600 mg

Treatment N n %Difference

(%)*SE Diff

(%)*

80% CI- Lower (%)*

80% CI- Upper (%)*

LRV 500mg QD 65 51 79 -9 7 -18.1 0.8LRV 750mg QD 65 51 79 -8 7 -17.0 1.2EFV 600mg QD 63 54 86 NA NA NA NA

Week 48Analysis:

*Cochran-Mantel-Haenszel estimates were adjusted for randomization variables of screening HIV-1 RNA level and geographic region. A 2-sided 80% confidence interval was used. NA, not applicable; SE, standard error.

54/63 (86%)51/65 (79%)51/65 (79%)

Efficacy results through Week 48 (plasma HIV-1 RNA <50 c/mL, ITT, NC=F)

8

0102030405060708090

100

Efficacy by screening plasma HIV-1 RNA and geographic region (ITT, NC=F)

LRV 750mgLRV 500mg EFV 600mg

% s

ubje

cts

wit

h pl

asm

a H

IV-1

RNA

<50

c/m

L th

roug

h W

eek

48

45 44 41 20 21 22 47 43 39 18 22 24N=

8086 88

81 84 87

75

62

82

7268

83

N=

<100,000 Region A≥100,000 Region BEU, LatinAmerica,Australia,Canada

SouthAfrica

9

0102030405060708090

100LRV 750mgLRV 500mg EFV 600mg

% s

ubje

cts

wit

h pl

asm

a H

IV-1

RNA

<50

c/m

L th

roug

h W

eek

48

31 30 26 16 13 13 14 14 15 4 8 9N=

8187 89

7986 87

8177

85

50

38

78

Region A EU, Latin America, Australia,

Canada

Region BSouth Africa

N=

<100,000 ≥100,000 <100,000 ≥100,000

Efficacy in Regions A and B by screening plasma HIV-1 RNA (ITT, NC=F)

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LRV 750 = 195 cells/mm3

LRV 500 = 191 cells/mm3

EFV = 188 cells/mm3

Baseline was the average of all the values obtained predose

Change from baseline CD4+ cell count (cells/mm3) (LOCF, ITT)

0 4 8 12 16 24 32 40 480

50

100

150

200

250

Time (weeks)

Mea

n ch

ange

from

bas

elin

e (c

ells/

mm

3 )

LRV 500 mg (N=65)LRV 750 mg (N=65)EFV 600 mg (N=63)

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Resistance analysis through 48 weeksTreatment Clade On-treatment failure

population genotype2On-treatment failure

FC IC50

LRV EFV FTC TDF1 500 mg QD B M184M/I/V, K101E, V108I, H221H/Y 56 3.9 >MAX 0.62 500 mg QD B M184M/I/V, Y188Y/H, F227F/L,

L234L/I3 36 1.6 >MAX 0.53 500 mg QD B M184V, V90I4, F227C5 69 5.2 >MAX 0.64 500 mg QD C NM 0.8 0.6 1.3 1.01 750 mg QD C M184V, V106M, F227L* 114* 11* >MAX* 0.4*2 750 mg QD1 C NM 0.5 0.5 1.2 0.83 750 mg QD B NM 0.9 0.9 0.9 0.84 750 mg QD1 B NM 3.6 2.3 0.8 1.15 750 mg QD C NM* 1.3* 0.7* 1.3* 1.1*1 EFV B K103N 1.3 11 1.3 1.32 EFV B NM 0.8 0.6 1.0 1.03 EFV C NM 0.8 0.4 1.2 1.0FC, fold-change IC50 to wild-type reference strain; FTC, emtricitabine; TDF, tenofovir; EFV, efavirenz; NM,

no mutation1Plasma HIV-1 RNA <500 c/mL 2Confirmation of failure, E_Term or Week 48 sample3 M230I (study exclusion mutation) detected at screening4V90I detected at screening and baseline (baseline FC=2.1)5P225P/L detected at failure* Sample taken outside of 48-week windowAlso see Craig, C et al. Minority species resistance present at screening does not affect ourcomes at week 48. IAS Rome. Poster MOPE161.

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Summary of clinical adverse events (AEs)

Number of Subjects with AE, n (%)

LRV 500 mgN = 65

LRV 750 mg N = 65

EFV 600 mg N = 63

Any AE 52 (80) 56 (86) 58 (92)

Serious AE 4 (6) 5 (8) 4 (6)

Grade 3 or 4 AE 4 (6) 9 (14) 14 (22)

Discontinuation due to AE 3 (5) 3 (5) 5 (8)

Deaths 0 1 (2) 0

Category C Events 0 2 (3) 0

Malignancies 0 1 (2) 1 (2)

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All-causality AEs(All severities, ≥10% incidence in any group)

*Includes reported terms of: rash erythematous, rash macular, and rash pruriticBold text indicates AEs of interest for which there was a higher rate of occurrence in either (i) both LRV groups versus EFV, or (ii) EFV versus both LRV groups

Number of Subjects with AE, n (%)

LRV 500 mgN = 65

LRV 750 mg N = 65

EFV 600 mg N = 63

Nausea 15 (23) 27 (42) 8 (13) Headache 15 (23) 11 (17) 9 (14) Abnormal dreams 5 (8) 5 (8) 12 (19) Dizziness 5 (8) 4 (6) 13 (21) Rash* 3 (5) 1 (2) 7 (11) Abdominal pain 2 (3) 6 (9) 7 (11) Vomiting 2 (3) 10 (15) 9 (14) Diarrhea 10 (15) 10 (15) 10 (16) Insomnia 5 (8) 9 (14) 5 (8) Influenza 3 (5) 7 (11) 7 (11) Nasopharyngitis 7 (11) 1 (2) 1 (2) Pharyngitis 2 (3) 2 (3) 6 (10) Upper respiratory tract infection 8 (12) 11 (17) 9 (14)

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Number of subjects with Grade 3-4 AE treatment-related, n (%)

LRV 500 mgN = 65

LRV 750 mg N = 65

EFV 600 mgN = 63

Any Grade 3-4 AE 2 (3) 3 (5) 8 (13)

ALT or AST increased 1 (2) 0 2 (3)

Other lab abnormality 1 (2) 0 3 (5)

Gastrointestinal disorder 0 1 (2) 0

Neoplasm/Malignancy 0 0 1 (2)Nervous system or psychiatric disorder 0 1 (2) 3 (5)

Other 0 1 (2) 1 (2)

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase

Grade 3 or 4 AEs (treatment-related)

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Summary of laboratory abnormalities1

(Grade 3 or 4)Laboratory parameter, n (%)

LRV 500 mg N =

64

LRV 750 mg N = 65

EFV 600 mg N = 63

Hemoglobin (<7.4 g/dL)

1 (2) 0 1 (2)

Platelets (<50K/mm3) 0 0 1 (2)White Blood Cell Count (<1500/mm3)

1 (2) 0 0

Absolute Neutrophil Count (<749/mm3)

1 (2) 1 (2) 0

Total Bilirubin (>2.6x ULN) 1 (2) 0 0Aspartate aminotransferase (≥5.1x ULN)

1 (2) 2 (3) 1 (2)

Alanine aminotransferase (≥5.1x ULN)

1 (2) 2 (3) 3 (5)

Creatinine (≥1.9x ULN) 0 1 (2) 0Albumin (<2 g/dL) 1 (2) 0 0Potassium (≤2 mEq/L) 1 (2) 0 0Creatine Kinase (>10x ULN) 1 (2) 2 (3) 2 (3)LDL cholesterol (>190 mg/dL) 0 0 2 (3)Total cholesterol (>300 mg/dL) 0 0 1 (2)Lipase* (≥3.1x ULN) 0 1 (5) 0

*For LRV 500 mg, LRV 750 mg and EFV groups, N=29, 19 and 29, respectively (lipase was tested only if amylase was elevated)LDL, low-density lipoprotein; ULN, upper limit of normal1DAIDS – Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 2004

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Effect on serum lipids:LRV did not increase TC, LDL-C or TG

Parameter, Least Squares Mean (SE)

LRV 500 mgN = 48

LRV 750 mg N = 51

EFV 600 mg N = 48

Total cholesterol (mg/dL) 0.9 (3.7) -4.2 (3.5) 15.5 (3.6)LDL cholesterol (mg/dL) -1.7 (3.0) -4.6 (2.9)* 4.0 (2.9)HDL cholesterol (mg/dL) 2.8 (1.3) 1.2 (1.3) 9.3 (1.3)Ratio total/HDL cholesterol 0.24 (0.24) -0.06 (0.23) -0.3 (0.23)Triglycerides (mg/dL) -1.5 (8.2) -3.1 (7.8) 10.6 (7.8)

Change from baseline at 48 weeks

HDL, high-density lipoprotein*N=50Screening HIV-1 RNA level (<100K or ≥100K c/mL), geographic region, and baseline fasting measurements (continuous) were included as covariates)

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Summary & Conclusions

• Both LRV doses achieved similar viral load suppression to EFV– 51/65 (79%) for both doses LRV, 54/63 (86%) for EFV

• Resistance profiles consistent with in vitro data

• LRV+TDF/FTC showed a different AE profile from EFV– More nausea in LRV arms– Fewer G3/4, neuropsychiatric AEs (compared to EFV)– Lab AEs infrequent– Neutral effects on lipid levels

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Acknowledgements• All patients participating in the A5271015 study• Data Monitoring Committee members• Pfizer and ViiV Healthcare team members• Investigators and study site staff

Canada Jean-Guy Baril Jason Brunetta Benoit TrottierSouth AfricaLerato Mohapi Richard Kaplan Ezio Baraldi Mohammed S. Rassool Gulam Hoosain Latiff Mariette E. BotesAustraliaMark T. Bloch David A. Cooper Julian HJ Elliott

United KingdomAlan Winston Anton Pozniak Martin J. Fisher Margaret A. Johnson Lydons WilkinsPolandAndrzej Horban Tomasz Smiatacz Waldemar Halota Jan KuydowiczSwitzerlandRainer Weber Pietro Vernazza Enos Bernasconi

ItalyAdriano Lazzarin Antonella D'Arminio Monforte Giovanni Di PerriArgentina Pablo Scapellato Edmund KarlaMexico Alejandra Romero-Mora