Future Applications of Antiretroviral Agents in Development Kathleen E. Squires, MD Professor of Medicine and Director Division of Infectious Diseases.

Future Applications of Antiretroviral Agents in Development

Kathleen E. Squires, MD

Professor of Medicine and DirectorDivision of Infectious Diseases

Jefferson Medical CollegePhiladelphia, PA

Antiretroviral Drug Development Issues to Address

Current Limitations• Adherence• Toxicity• Activity• Resistance

Ideal Characteristics• Improve convenience• Improve tolerability• Reduce toxicity• Improve activity

– Wild-type virus– Resistant virus

• Penetrate reservoirs• Exploit new targets

Novel Agents in Clinical Development

PhaseReverse

Transcriptase

Inhibitors

Protease

Inhibitors

Entry

Inhibitors

Integrase/

Maturation

Inhibitors; Immunologics

II/III Etravirine (TMC 125) DarunavirMaraviroc

VicrivirocMK-0518

II BILR 355 BS TNX-355 GS 9137

I/II

Amdoxovir

Apricitabine

Rilpivirine (TMC 278)

BrecanavirAMD 070

PRO 542

Bevirimat

CTLA4-mAb

I Fosalvudine PPL-100PRO 140

TAK 652

Preclinical 22 7 21 11

New Generation NNRTIs Etravirine (TMC125)

• Novel NNRTI designed to have a high genetic barrier to development of resistance[1]

• Potent in vitro antiviral activity against:– Wild-type and NNRTI resistant HIV-1[2]

– Clinical isolates resistant against approved NNRTIs[2]

• In a 7-day clinical trial, TMC125 monotherapy produced a median viral load change of –0.89 log10 copies/mL in patients on failing NNRTI therapy[3]

• DUET 1 and 2 studies ongoing: etravirine vs placebo, with DRV/r and OBR in patients with both NNRTI and PI resistance

• Expanded access just opened

1Vingerhoets J, et al. J Virol 2005 Oct;79(20):12773-12782.2Andries K, et al. Antimicrob Agents Chemother 2004 Dec;48(12):4680–4686.

3Gazzard BG, et al. AIDS 2003 Dec 5;17(18):F49–F54.

TMC125-C223Study Design

*Active control: best available regimen from licensed agents†Optimized background regimen: investigator selected NRTIs ± LPV/r ± T-20

Active control*

TMC125 400 mg BID + OBR†

TMC125 800 mg BID + OBR†

N = 199

Screening Treatment

4 weeks 48 weeks

• Primary Objective: – Proportion of patients with ≥ 1 log10 reduction in HIV RNA from baseline to Week 24

Cohen C, et al. 12th Annual Conference of BHIVA; Mar 29-Apr 1, 2006; Brighton, UK. Abstract P2.

0 20Percentage with response

40 60 80 100

23%

400 mg BID (n = 80) 800 mg BID (n = 79) Active control (n = 40)

22%0%

<50 copies/mL

<400 copies/mL

≥1 log reductionin HIV RNA

28%30%

8%

31%34%

8%

P < .001P < .001

P = .036P = .009

P = .016P = .004

TMC125-C223Virologic Response* at Week 48

Cohen C, et al, XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

* Time-to-Loss of Virologic Response (TLOVR)

P-values versus active control

TMC125, Phase IIb formulation TF035

TMC125-C223Number of NNRTI Mutations and Virologic Response at Week 48

• Patients discontinuing the trial for any reason had their VL response imputed as no change from baseline (NC = F)

Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

*All patients had NNRTI mutations from prior genotyping

Baseline NNRTI mutationsin TMC125 800 mg BID

Mea

n c

han

ge

in l

og

10 V

L

TMC125 800 mg

BID

n = 79

Activecontrol 0* 1 2 3n = 40

–1.01

–0.14

–1.67

–1.38

–0.9

n = 30

–0.54

0

–0.5

–1.0

–1.5

–2.0

n = 14 n = 19 n = 16

TMC125, Phase IIb formulation TF035

Baseline NNRTI Mutations Associated With TMC125 FC >10 (Arbitrary Threshold)

• No single NNRTI mutation was associated with mean FC >10 (arbitrary threshold) to TMC125

• Frequency of combinations of NNRTI mutations associated with mean TMC125 FC >10 was low (12%)

• Each of the following mutations, always in combination with up to four other mutations, were associated with mean FC >10– K101P, V179E, V179F, Y181I, Y181V, G190S, M230L

– For V179E, V179F, G190S, M230L: additional mutations always included Y181C when FC >10

• These mutations were previously identified in vitro to be associated with increased FC to TMC125

1. Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

2. Vingerhoets J ,et al. J Virol. 2005 Oct;79(20):12773-82.

TMC125, Phase IIb formulation TF035

Targets for Antiretroviral Therapy

Reverse Transcriptase

Inhibitors

Protease Inhibitors

Integrase Inhibitors

EntryInhibitors

PIs

Maturation Inhibitors

NRTIs,NNRTIs

Attachment Inhibitors, Coreceptor Antagonists

Fusion Inhibitor

HIV Entry Inhibitors

• New class of therapy • Works early in life cycle of the HIV virus• Inhibits fusion of viral particle with cell • Subcutaneous injection• Potent antiviral, but need other active antivirals

for best effect• Injection site reactions

Phase II Study of TNX-355A Novel Entry Inhibitor

• 48-week phase II study– 3-class experienced (n=82)

• Treatment arms– OBR vs. TNX-355 + OBR

• 15 mg/kg IV q2wks• 10 mg/kg IV qwk x 8 wks, then

10 mg/kg q2wks

– CD4 response:• OBR: +5 cells/mm3

• 10 mg/kg: +9 cells/mm3

• 15 mg/kg: +51 cells/mm3

• Well tolerated, no serious ADR related to drug, no ISRs

• Results sustained to Wk 48

Norris D, et al. 45th ICAAC. Washington, DC, 2005. Abstract LB2-26Tanox Inc. News Release May 2, 2006.

-0.8

-0.4

0

-1.2Mea

n C

hang

e in

HIV

-1 R

NA

at

Wee

k 24

(lo

g 10

copi

es/m

L)

OBR Alone

15 mg/kg

10 mg/kg

-0.20

-0.95(P = .003)

-1.16(P < .001)

TNX-355 + OBR

HIV Tropism and Disease Progression

Courtesy GSK interactive CD "Exploring an allosteric world: CCR5 entry inhibitors and HIV"

R5 Mixed/DualC

D4

Cel

l C

ou

nt

Time

Am

ou

nt o

f Viru

s

↑ X4

CCR5-tropic HIV

CXCR4-tropic HIV

Dual-tropic HIV

* Less than 10% of a tropism is not detectable with current tropism assay

Limit of tropism assay detection*

• Randomization of 80 HIV infected patients with CCR5 tropic virus– CD4 >250 cells/mm3

– VL >5000 copies/mL0.5

-1.5

-1.0

-0.5

0

Days

300 mg BID

Placebo 15

Placebo 07

25 mg QD

50 mg BID

100 mg QD

100 mg BID

150 mg Fast

150 mg Fed

300 mg QD

DosingMed

ian

VL

Ch

ang

e F

rom

B

L (

log

10 c

op

ies/

mL

)

0 5 10 15 20 25 30 35 40

-2.0

• Doses >100mg/d had > 1.0 log10

decrease

• Small CD4 count with all doses

• 61/63 had CCR5 tropic virus at BL remained CCR5 tropic at follow up

– 1 reverted to CCR5 topic at day 40

– 1 persisted >6 mo post study with no evidence of clinical progression

Fatkenheuer G et al. XV IAC. Bangcock, Thailand. Abstract TuPeB4489

CCR5 Inhibitors in Development Maraviroc

Phase IIb Pilot Study Evaluating the Safety of Maraviroc in Patients with Non-R5 HIV-1

• Randomized, double-blind, placebo-controlled study• Selection criteria:

– D/M-tropic, X4-tropic or indeterminate tropism phenotype– Antiretroviral experienced and/or multi-class resistance – At least one active drug in OBT

*OBT = 3 to 6 ARVs (note PK boosting doses of RTV will not be counted as an ARV)**150 mg maraviroc with PIs provides equivalent dose to 300 mg without PIs

Screening and

randomization

OBT* + MARAVIROC (150 mg** BID)

OBT* + MARAVIROC (150 mg** QD)

OBT* + Placebo

Weeks

Primary efficacy endpoint

04-6 Weeks

24 48

Maraviroc: Efficacy Results

All treated patients with D/M-tropic HIV-1

Placebo + OBT

n = 58

MVC QD + OBT

n = 57

MVC BID + OBT

n = 52

Mean decrease in HIV-1 RNA (log10c/mL)* -0.97 -0.91 -1.20

Treatment diff (MVC-OBT) in HIV-1 RNA decrease (log10c/mL) (97.5% CI)

+0.06 (-0.53, +0.64)

-0.23(-0.83, +0.36)

HIV RNA < 400 c/mL (%)

HIV RNA < 50 c/mL (%)

24.1

15.5

24.6

21.1

30.8

26.9

Mean decrease in HIV-1 RNA in patients using enfuvirtide** (log10c/mL)

-0.89 -1.26 -1.44

OBT - optimized background therapyD/M - dual/mixed tropic *Primary endpoint **LOCF

Mayer H, et al IAC 2006. Abstract THLB0215.

On the HorizonIntegrase Inhibitors

• Integrase inhibitors– MK-0518– GS 9137

Integrase Inhibitor (MK-0518)Phase IIa 10-Day Dosing Study

• Phase IIa, placebo-controlled, monotherapy study– 35 treatment-naïve patients

– Baseline HIV RNA• 4.53 to 4.97 log10 copies/mL

• MK-0518– Doses: 100, 200, 400, 600 mg bid

• At day 10– HIV RNA <400 copies/mL: >50%

– No significant change in CD4 cell count from baseline

– Most common adverse events• Headache, fatigue, and dizziness

Change in HIV RNAat Day 10

(log10 copies/mL)

Placebo (n=7) -0.2

MK-0518 (mg bid)

100 (n=7) -1.9

200 (n=7) -2.0

400 (n=6) -1.7

600 (n=8) -2.2

Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6.

MK-0518: Phase IIb (Protocol 005)

N=167VL ≥ 5000CD4 ≥ 50

Resistant to ≥ 1 NRTI, NNRTI, PI Placebo

+ OBRN = 43

MK-0518 200mg bid

+ OBR

N = 40

MK-0518 400mg bid

+ OBR

N = 42

MK-0518 600mg bid+ OBRN = 42

• Treatment arms similar at baseline

• Mean duration of HAART: 9-11 yrs

• Multicenter, randomized, double blind

Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

• Mean VL: 4.6-4.8 log10 copies/mL

• Use of ENF in OBR: 33% to 38% – Patients with no active PIs in OBR: 84% to 98%

– Mean CD4: 220-283 cells/mm3

MK-0518Virologic Suppression Through Week 16

Treatment† n % < 400 copies

MK-0518 200 mg BID 25 84

MK-0518 400 mg BID 28 73

MK-0518 600 mg BID 28 67

Placebo 27 24

CI = Confidence Interval.† All subjects received OBT in addition to MK-0518 or placebo.

Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

MK-0518: Adverse Events

• ADRs: similar to placebo• Most common ADR

– Diarrhea, nausea, fatigue, ISRs, headache, pruritus– Occurring in >5% of 2 patients per arm

Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

MK-0518: Study DesignPotent Activity of Integrase Inhibitor in Treatment-Naive Patients

Part I Design• 8 patients each received MK-0518 at 600, 400, 200, or 100 mg

bid or placebo for 10 days monotherapy

• 30 patients in addition each received one of the MK-0518 doses plus TFV+3TC, or efavirenz plus TFV+3TC, for a total of 38 patients in each arm

Part II Design• Part I patients continued at same dose in Part II

~150 additional patients randomized for Part II

Endpoints• HIV RNA and CD4 counts

MK-0518 vs EfavirenzHIV RNA < 50 copies/mL at Week 24 (NC = F)

 HIV RNA levels %

(95% CI)

Treatment (mg) N<400

copies/mL<50 copies/mL

MK-0518 BID 100 18 89 (65, 99) 88 (64, 99)*

MK-0518 BID 200 18 100 (82, 100) 100 (82, 100)

MK-0518 BID 300 17 94 (71, 100) 94 (71, 100)

MK-0518 BID 400 17 100 (81, 100) 94 (70, 100)*

Efavirenz BID 600 15 93 (68, 100) 86 (57, 98)*

*One patient was excluded pending additional test results

Markowitz M, et al. IAC 2006. Abstract THLB0214.

Integrase Inhibitor (GS 9137)10-Day Monotherapy Study

• Phase IIb, placebo-controlled, monotherapy study

– 40 treatment-naïve and treatment-experienced patients

– Baseline

• HIV RNA: 4.75 log10 copies/mL

• CD4: 442 cells/mm3

• At day 10

– >1 log10 reduction in HIV RNA

• GS-9137: 83%

• Placebo: 0%

– No serious adverse events and no study drug discontinuations

– Most common adverse events• Fatigue, diarrhea, headache, nausea

Change inHIV RNAat Day 10

(log10 copies/mL)

Placebo -0.13

GS-9137

800 mg qd -0.89*

200 mg bid -1.44*

400 mg bid -1.98*

800 mg bid -1.78*

50 mg qd + RTV 100mg qd

-2.03*†

DeJesus E, et al. 13th CROI. Denver, 2006. Abstract 160LB.

*P<0.01 versus placebo.†P<0.05 versus 800 mg qd.

Maturation InhibitorPA-457

• First maturation inhibitor• Data from a double blind, placebo controlled single

dose study of 75mg, 150mg and 250mg and placebo (all n=6); naïve or of-treatment for >4 weeks; two subjects had MDR

• Dose related response with median reduction at the highest dose of -0.51 log10 and a greatest decline of -0.73 log10. 8/12 in higher doses >0.3 log10

• Return to baseline was inhibited for at least 20 days in the 250mg dose arm

Martin D, et al. CROI 2005. Abstract 159.

Maturation Inhibitor (PA-457)Phase II Dosing Study

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Lo

g10

Co

pie

s/m

L

25 50 100 200

PA-457 mg qd

0.046

-0.174

-0.483

-1.05

Change in HIV RNA at Day 11• Phase II, placebo-controlled, monotherapy study– 32 treatment-naïve patients

– Baseline• HIV RNA: 4.73 log10 copies/mL

• CD4: 441 cells/mm3

• Oral doses of PA-457– 25, 50, 100, 200 mg qd

• At day 11– AUC and trough levels were

significantly associated with antiviral response (P<0.01)

Smith P, et al. 13th CROI. Denver, 2006. Abstract 52.

New Antiretroviral AgentsConclusions

• Newer drugs are needed to improve convenience, tolerability and activity (wild-type and resistant virus)

• Promising agents are in development both in existing classes (NNRTI, PI) and new classes (e.g, entry and integrase inhibitors)

• Further basic and clinical research is needed