Emerging Therapies for HIV Multiple Drug · Autologous Delipidated HIV Therapeutic Vaccine Lipid...

1

Emerging Therapies for Emerging Therapies for HIV Multiple Drug HIV Multiple Drug

ResistanceResistanceNelson Nelson VergelVergel

www.salvagetherapies.orgwww.salvagetherapies.org

This information (and any accompanying printed This information (and any accompanying printed material) is not intended to replace the attention or material) is not intended to replace the attention or

advice of a physician or other health care professional. advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, Anyone who wishes to embark on any dietary, drug,

exercise, or other lifestyle change intended to prevent exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first or treat a specific disease or condition should first

consult with and seek clearance from a qualified health consult with and seek clearance from a qualified health care professional.care professional.

The AIDS pandemicThe AIDS pandemicAdults and children infected with Adults and children infected with

HIV/AIDS, end 2002HIV/AIDS, end 2002

North America980,000

North America980,000

Caribbean440,000Caribbean440,000

Latin America1,500,000

Latin America1,500,000

North Africa& Middle East

550,000

North Africa& Middle East

550,000

Sub-Saharan Africa29,400,000

Sub-Saharan Africa29,400,000

East Asia & Pacific

1,200,000

East Asia & Pacific

1,200,000

S & SE Asia6,000,000

S & SE Asia6,000,000

Australia& New Zealand

15,000

Australia& New Zealand

15,000

Western Europe

570,000

Western Europe

570,000

Eastern Europe& Central Asia1,200,000

Eastern Europe& Central Asia1,200,000

3.4%3.4%

4.8%4.8% 5.6%5.6%

11.1%11.1%

13.2%13.2%

13.5%13.5%

15.8%15.8% 17.8%17.8%

20.8%20.8%

29.0%29.0%

2001-02 increase

Source: UNAIDS

Availability of HIV Medications in the World

Source: WHO,

http://www.who.int/3by5/en/

Coverage

Menos del 10%No hay informes de personas en tratamiento

HIV Medications Have HIV Medications Have Decreased The Death RateDecreased The Death Rate

NNRTI

’’8787 ’’9191 ’’9292 ’’9494 ’’9595 ’’9696 ’’9797 ’’9898 ’’9999 ’’0000’’8888 ’’8989 ’’9090

NRTINRTI

PIPI

Approved AntiretroviralsApproved Antiretrovirals

RetrovirRetrovir

NorvirNorvir

InviraseInvirase

CrixivanCrixivan

FortovaseFortovaseKaletraKaletraViraceptViracept

ZiagenZiagenCombivirCombivir

VidexVidex

HividHivid

ZeritZerit

EpivirEpivir

TrizivirTrizivir

Rescriptor

SustivaViramune

’’0101

VireadVireadEmtrivaEmtriva

ReyatazReyataz

’’0202 ’’0303’’9393

AgeneraseAgeneraseFIFIFUZEONFUZEON

Retrovir, Epivir, Combivir, Ziagen, Retrovir, Epivir, Combivir, Ziagen, AgeneraseAgenerase, , LexivaLexiva and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, and Trizivir are trademarks of GlaxoSmithKline. Videx, Zerit, Sustiva and Reyataz are Sustiva and Reyataz are trademarks of Bristoltrademarks of Bristol--Myers Squibb. Norvir and Kaletra are registered trademarks of AbMyers Squibb. Norvir and Kaletra are registered trademarks of Abbott. Crixivan is registered trademark of Merck. bott. Crixivan is registered trademark of Merck. Viramune is registered trademark of Boehringer Ingelheim. ViraceViramune is registered trademark of Boehringer Ingelheim. Viracept and Rescriptor are registered trademarks of Agouron. Viread apt and Rescriptor are registered trademarks of Agouron. Viread and nd Emtriva are trademarks of Gilead. Emtriva are trademarks of Gilead. HividHivid, Invirase, Fortovase and FUZEON are registered trademarks of Ro, Invirase, Fortovase and FUZEON are registered trademarks of Roche Laboratories.che Laboratories.

LexivaLexiva

AptivusAptivus

0505

2

RNARNA

ReverseReversetranscriptasetranscriptase

ProteaseProtease

DNADNA

NucleusNucleus

Protease inhibitorsReverse transcriptase inhibitors:NRTI (nucleosides, nucleotides)

NNRTI

EntryInhibitors:

Fusion, CD4, CCR5CXCR4

Targets of HIV TherapyTargets of HIV Therapy

CDCD44+ T+ T--CellCell

HIV

Integrase Inhibitors

Maturation Inhibitors

Emerging Drugs for Treatment Emerging Drugs for Treatment Experience PatientsExperience Patients

Late Phase ILate Phase I

GSKGSK’’ss GW695634GW695634-- NonNon--nucleosidenucleosideGSKGSK’’ss GW64035XGW64035X-- ProteaseProtease

Phase IIPhase IIPanacosPanacos’’ PA 457 maturation inhibitorPA 457 maturation inhibitorAnormedAnormed’’ss AMDAMD--070 (CRX4 inhibitor) 070 (CRX4 inhibitor) IncyteIncyte’’ss DD--d4FC (old d4FC (old ReversetReverset))-- NucleosideNucleoside

Phase III Phase III (1(1--2 years from approval if everything is ok)2 years from approval if everything is ok)MerckMerck’’s s IntegraseIntegrase Inhibitor MKInhibitor MK--05180518PfizerPfizer’’s UKs UK--427,857 427,857 –– MaravirocMaraviroc (CCR5 Entry Inhibitor )(CCR5 Entry Inhibitor )ScheringSchering’’s s SCHSCH--D (D (VicrivirocVicriviroc)) (CCR5 Entry Inhibitor)(CCR5 Entry Inhibitor)TanoxTanox’’ss TNX 355 (CD4 attachment inhibitor) TNX 355 (CD4 attachment inhibitor) TibotecTibotec’’ss TMC 114 Protease (also TMC 114 Protease (also Expanded AccessExpanded Access now)now)TibotecTibotec’’ss TMC 125 NNRTI (combo study with TMC 114) TMC 125 NNRTI (combo study with TMC 114)

HIV Therapeutic Vaccines in DevelopmentHIV Therapeutic Vaccines in Development

PreclinicalPreclinicalLipid SciencesLipid SciencesAutologousAutologous DelipidatedDelipidated HIV Therapeutic VaccineHIV Therapeutic Vaccine

Phase IPhase IFITFIT--BIOTECHBIOTECHGTUGTU--NefNef DNA vaccineDNA vaccine

PreclinicalPreclinicalCelCel--SciSciHIV L.E.A.P.S. HIVHIV L.E.A.P.S. HIV--1 p17 constructs (L.E.A.P.S. 101B, 1 p17 constructs (L.E.A.P.S. 101B, 101C, 102B and 102C)101C, 102B and 102C)

PreclinicalPreclinicalUnited BiomedicalUnited BiomedicalSynthetic peptide Synthetic peptide immunogensimmunogens

Phase IPhase IViraxViraxDNA/DNA/fowlpoxfowlpox primeprime--boostboost

Phase IPhase IAventis PasteurAventis PasteurTat vaccineTat vaccine

Failed phase III, remains under Failed phase III, remains under investigation in context of investigation in context of STIsSTIs

Immune Response CorporationImmune Response CorporationRemuneRemune

Phase I/IIPhase I/IICobra Pharmaceuticals, Cobra Pharmaceuticals, ImpfstoffwerkImpfstoffwerk DessauDessau--TornauTornau GmbH GmbH (IDT), Oxford University/MRC(IDT), Oxford University/MRC

DNA/MVADNA/MVA

PreclinicalPreclinicalGlaxoSmithKlineGlaxoSmithKlineTat/Nef/gp120 in ASO2A adjuvantTat/Nef/gp120 in ASO2A adjuvant

PreclinicalPreclinicalGlobeimmuneGlobeimmuneHIVAXHIVAX

PreclinicalPreclinicalKathy Kathy GrovitGrovit--Ferbas/UCLAFerbas/UCLAWholeWhole--killed (killed (pseudovirionspseudovirions))

PreclinicalPreclinicalWyethWyeth--AyerstAyerstDNA + ILDNA + IL--12 or IL12 or IL--1515

Phase IPhase IEpimmuneEpimmuneMultiMulti--epitopeepitope DNADNA

Phase IPhase IUniversity of PittsburghUniversity of PittsburghAutologousAutologous dendriticdendritic cell HIV vaccination w/conserved cell HIV vaccination w/conserved HIVHIV--derived peptidesderived peptides

Phase IPhase IACTG/AventisACTG/AventisAutologousAutologous dendriticdendritic cells pulsed w/ALVACcells pulsed w/ALVAC

Phase I in HIV Phase I in HIV seronegativeseronegative volunteersvolunteersAlphaVaxAlphaVaxVEE VEE repliconreplicon

Phase IPhase IMerckMerckMRKDNAMRKDNA

Phase I/IIPhase I/IIMerckMerckMRKAd5MRKAd5

Phase IPhase IBavarian Nordic/Bavarian Nordic/EpimmuneEpimmuneMVAMVA--mBN32mBN32

Phase IPhase IBavarian NordicBavarian NordicMVAMVA--BNBN--NefNef

Phase IPhase IVRC/NIAIDVRC/NIAIDVRCVRC--HIVDNA009HIVDNA009--0000--VP Gag/VP Gag/Pol/Nef/multicladePol/Nef/multiclade EnvsEnvs(A, B, C)(A, B, C)

PreclinicalPreclinicalResearch Institute for Genetic & Human Therapy (RIGHT)Research Institute for Genetic & Human Therapy (RIGHT)DermavirDermavir

Phase IIPhase IIAventis Pasteur/ANRSAventis Pasteur/ANRSLipopeptidesLipopeptides

Phase IIPhase IIAventis PasteurAventis PasteurALVAC (vCP1452)ALVAC (vCP1452)

Phase IIPhase IICell Cell GenesysGenesysCD4zeta modified CD4 and CD8 T cellsCD4zeta modified CD4 and CD8 T cells

Phase IPhase IEUFETS AGEUFETS AGCD4 T cells CD4 T cells transducedtransduced with M87o viral with M87o viral entry inhibitorentry inhibitor

Phase IPhase IEnzoEnzo BiochemBiochemHGTV43HGTV43

Phase IIPhase IIJohnson & Johnson & JohnsonJohnsonRibozymesRibozymes (RRz2)(RRz2)

Phase IPhase IVIRxSYSVIRxSYSVRX496 VRX496 lentivirallentiviral vectorvector

Gene Therapies Gene Therapies

clinicaloptions.com/hiv

Choosing and Using Antiretrovirals for Multiclass-Experienced Patients

PA-457

PIs

NNRTINRTI

Maturation inhibitorsCCR5

Inhibitors

Integrase Inhibitors

TMC278

TMC125

D-d4FC

TMC114

GW640385

Integrase inhibitors

Entry inhibitors (anti-gp120, CCR5)

GW695634

CXCR4 Inhibitors

?

Timeline for New Antiretrovirals

20092008200720062005

C12

Increasing prevalence of drug resistance

Prevalence of resistance increasing in treatment-naïve and experienced patient populations

HCSUS cohort (1) showed 42% prevalence of PI resistance in samples from 1099 viremic patients

CDC surveillance of recently infected treatment-naïve patientsshowed 15.2% prevalence of resistance-associated mutations

CHIC study showed 25% risk of resistance over 6 years in patients starting 3-drug antiretroviral therapy

1. Richman, D et al. AIDS 2004; 18: 1393 2. Bennett D, et al. 12th CROI 2005, Abstract #674.

3

HIV POSITIVE PEOPLE IN THE USHIV POSITIVE PEOPLE IN THE US--FIRST, SECOND, THIRDFIRST, SECOND, THIRD

LINE AND SALVAGELINE AND SALVAGE

Treatment Strategies for Optimizing the Benefits of New Agents

How to Switch: Use at least 3 fully effective drugs

Katzenstein/Albrecht AIDS 2003

PSS: Phenotypic Susceptibility ScorePSS: Phenotypic Susceptibility Score

At least 3 active drugs leftAt least 3 active drugs left

From 2From 2--3 active drugs left3 active drugs left

Less than 2 drugs leftLess than 2 drugs left

Main Objective of Salvage Therapy:Main Objective of Salvage Therapy:

If possible, patients with multiple drug resistanceIf possible, patients with multiple drug resistanceshould should not not be exposed to be exposed to

monotherapy of any kind, or to "virtual monotherapy", monotherapy of any kind, or to "virtual monotherapy", where one new drug is added to a failing regimen for where one new drug is added to a failing regimen for

any appreciable length of timeany appreciable length of time.

Maintain mutationsDecrease fitness

Delay progression

Accumulate newmutations

Develop resistance to drugs in

development

Continued Therapy in Patients With Virologic Failure: A Delicate Balance

Add New Active DrugAdd New Active DrugKeep Current RegimenKeep Current Regimen(Holding Pattern)(Holding Pattern)

In combination therapy, only the active drugs countA new drug is not necessarily an active drugAdding a new class is associated with better outcomesWhen to use a new drug, and when to waitWaiting: Choosing a “holding regimen”The role of replication capacity

Considerations for Salvage Therapy

4

Fusion Inhibition: Optimal Use of Fuzeon (T-20)

Kaletra (TORO), Aptivus (RESIST) and TMC 114 (POWER) with or without Fuzeon- VirologicResponse (Viral load reduction of 1 log or more)

24%

55%

20

40

60

80

100

<400 copies/ml

Patie

nts

(%)

TORO

LPV/rFUZEON + LPV/r

20

40

60

80

100

37%

67%

<50 copies/ml

Patie

nts

(%)

POWER

TMC114/rFUZEON + TMC114/r

≥1 log10 dropfrom baseline

37%

70%

20

40

60

80

100

Patie

nts

(%)

RESIST

TPV/rFUZEON + TPV/r

New Fuzeon Approaches

• New data show that after failing Fuzeon and stopping the drug for 16 weeks, some sensitivity returns

• After Fuzeon failure and interruption for 4 months, some clinicians are starting to use a pulsing mode with Fuzeon that lasts 4 weeks

• The reintroduction of Fuzeon (in those who have used it in the past) when starting one or more new active drugs needs to be investigated

Predictors of Best Therapeutic Response to Fuzeon (96 week data)Factors associated with ↑ likelihood of achieving HIV-1 viral load < 400 copies/mL in both arms

Patients receiving Fuzeon consistently had better virologic and immunologic outcomesThose with higher CD4 cells, lower viral loads and who started one or more active agents did better on the drug

< .00011.6-3.32.3≥ 2 active ARVs in OB< .00011.6-3.42.4Prior experience with ≤ 10 ARVs.00321.2-2.61.8Baseline HIV-1 RNA < 100,000 copies/mL

< .00011.5-3.12.1Baseline CD4+ cell count > 100 cells/mm3

P Value95% CIOdds Ratio

Variable


HIV/AIDS Update From Rio

Needle-Free Injection System for Administration of Enfuvirtide

Montaner J, et al. IAS 2005. Abstract WeFo0205.

Use of needle-free gas-powered injection system

– Compared with standard needles and syringes

No significant differences in Fuzeon plasma levels

ISR(injection site reactions)-related signs and symptoms significantly reduced

24 pts evaluated reported that needle-free injector was similar or easier to use than needles

Needle Biojectiongas-powered

device

Biojector B2000

Not FDA approved yet with the Not FDA approved yet with the use of use of FuzeonFuzeon. In studies now. In studies now

Preliminary data show lower Preliminary data show lower incidence of injection site incidence of injection site reactionsreactions

To be approved by the FDA soon. To be approved by the FDA soon. Available at Available at BioScriptBioScriptPharmacies ( former Pharmacies ( former StatscriptStatscript))

Biojector injection Biojector injection techniquetechnique

Alternative method: Alternative method: Use of 31 Gauge, 5/16Use of 31 Gauge, 5/16”” insulin insulin

syringesyringe

5

Newest Protease Inhibitor: Aptivus (Tipranavir)



New Protease Inhibitors: Tipranavir (Aptivus)

Advantages– Available now

– More active in patients with highly PI-resistant HIV-1 than other available PIs

– Well characterized resistance profile

– Similar tolerability to other boosted PIs

– Excellent results with Fuzeon in very advanced patients

Disadvantages– If multiple PI mutations

present, may have limited barrier to resistance

– High triglycerides are common and elevated LFTs (liver function tests) may be more common vs other PIs

– Cannot combine with other PIs

– Some drug-drug interactions

27

RESIST StudiesTreatment Response

0

10

20

30

40

50

60

0 8 16 24

Trea

tmen

t Res

pond

ers

(%)

CPI/r (n=577)TPV/r (n=582)

Week 24: P <0.0001

Weeks

(41.2)

(18.9)

RESIST Studies Combined

≥1 log10 Viral Load Reduction, Confirmed, ITT: NCF

28

RESIST StudiesUndetectable Viral Load (<400, <50 copies/mL)

CPI/r (n=577)TPV/r (n=582)

ITT: NCF

05

10152025303540

0 8 16 24

Viro

logi

c R

espo

nse

VL <

400

Cop

ies/

mL

(%)

Week 24: P <0.0001

(34.2%)

(14.9%)

Weeks of Treatment

Viro

logi

c R

espo

nse

VL <

50 C

opie

s/m

L (%

)

05

10152025303540

0 8 16 24

Week 24: P <0.0001

(23.9%)

(9.4%)

29

RESIST StudiesVL Reduction and CD4 Increase

Weeks of Treatment

0 (0.25 log10 copies/mL)

-1.8-1.6-1.4-1.2

-1-0.8-0.6-0.4-0.2

0 8 16 24

Med

ian

VL lo

g 10

Cha

nge

From

Bas

elin

e

Week 24: P <0.0001

(0.80 log10 copies/mL)

ITT: LOCF

(+34 cells, range 3-87)

(+4 cells, range 0-61)

Week 24 difference: P <0.0001

Med

ian

Cha

nge

From

B

asel

ine

in C

D4+

Cel

l Cou

nt

05

10152025303540

0 8 16 24

CPI/r (n=577)TPV/r (n=582) 30

RESIST StudiesEfficacy Endpoints (Week 24)

NS34 (4.6%)25 (3.4%)AIDS Progression Events

<0.0001+ 4+ 34Median CD4+ Cell Change

<0.000154 (9.4%)139 (23.9%)VL <50 Copies/mL

<0.000186 (14.9%)199 (34.2%)VL <400 Copies/mL

<0.0001-0.25-0.80Total VL Reduction (log10)

<0.0001109 (18.9%)240 (41.2%)≥ 1 log10 VL Reduction (%)

P ValueCPI/r

N=577TPV/rN=582

All Patients in 24-Week Analysis Set

6

FUZEON naïve

No FUZEON FUZEONNo FUZEON FUZEON

FUZEON experienced

FUZEON in OB:

Prior FUZEON:

Best response in RESIST when FUZEON used for first time with TPV/r

0

20

40

60

80

100

% o

f pat

ient

s >1

log

VL d

eclin

e

TPV/rCPI/r

70%

18%

37%

18%

29%

7% 9%

31%

Cooper et al. CROI 2005. Abstract 560

N: 26 34 43 34 398 415 115 94

32

Drug Interaction ProgramAntiretroviral drugs

Seven common 3-drug ARV combinations (HIV+)

Dual-boosted PI regimens with LPV, SQV, and APV (HIV+)

ZDV, ddI, TDF, EFV (HIV-)

Drugs commonly used by HIV+ patientsEthinyl estradiol and norethindrone

Loperamide

Atorvastatin

Other studiesAntacid interaction

ADME

Clarithromycin

Fluconazole

Rifabutin

33

Hepatic Monitoring and Management Recommendations

Routine clinical and laboratory monitoring to detect liver abnormalities is recommended

Patients with chronic hepatitis B or C, or elevated LFTsat initiation of TPV/r therapy, require more frequent clinical and laboratory monitoring

Patients who are symptomatic in the setting of elevated LFTsshould have their TPV/r discontinued



New Protease Inhibitors: TMC114Advantages– Appears very active in patients

with highly PI-resistant HIV-1

– Substantially more than comparator PIs

– Side effect profile seems very similar to other boosted PIs

– Possibly a greater barrier to resistance even with highly PI-resistant virus

– Like Aptivus, those who start this drug with Fuzeon had better response

Disadvantages– Not yet approved but available

in expanded access

– Resistance information limited (Aptivus resistance?)

– Pooled results preliminary

– POWER1 subjects substantially less advanced

– Preliminary POWER2 results somewhat less robust



On the Horizon: Second Generation

Second-generation NNRTIs (Phase III)– TMC125 (etravirine)

– Phase II data show ↑ activity vs active control

– Phase III study enrolling now (DUET 1 and 2) in combination with TMC 114

– Rash may be the main side effect in 20 % of patients

Second-generation NRTIs (phase II)– D-d4FC (dexelvucitabine)

– AVX754

First Study in HIV History to Combine First Study in HIV History to Combine Two Investigational AgentsTwo Investigational Agents

TMC 114 (Protease) + TMC 125 (nonTMC 114 (Protease) + TMC 125 (non--nuke) DUET Studynuke) DUET StudyTMC 114+ TMC 125 + OBT (Optimized TMC 114+ TMC 125 + OBT (Optimized Background Therapy) Versus TMC 114 + Background Therapy) Versus TMC 114 + Placebo + OBTPlacebo + OBTTo start in January 06To start in January 06For more info:For more info:–– http://www.acria.org/clinical_trials/TrialsSearch/detail.ashttp://www.acria.org/clinical_trials/TrialsSearch/detail.as

p?StudyIdp?StudyId=1526&Tname=TMC+114+%26+TMC+125=1526&Tname=TMC+114+%26+TMC+125

7



On the Horizon: New ClassesIntegrase Inhibitors– MK-0518 (phase III)

▪ Phase II studies fully enrolled; BID dosing▪ Phase III enrolling in March▪ Potent agent that may reduce viral load significantly, specially when

used with TMC 114 (protease)

– GS-9137▪ Phase II studies in development

Maturation Inhibitors– PA-457

▪ Proof-of-principle study demonstrated short-term activity. Phase II to start late in 2006

CCR5 and CXCR4 Are Co-receptors for HIV Binding and Entry

TT--cell surfacecell surfaceCCR5

CD4

CXCR4

39

Prevalence of HIV Co-receptor Usage

17<183NaiveHomer cohortb

15085NaiveC & W cohortc

6094NaiveMaraviroc (UK-427,857) Phase 2a

12088NaiveGSKd

Experienced

Experienced

Population

48250ViroLogicf

34462TORO 1/2e

R5/X4X4R5Study/Source

a Data on file d Demarest et al. ICAAC 2004. Abstract H-1136b Harrigan PR et al. 15th IAC 2004. Abstract MoPeB3117 e Whitcomb et al. CROI 2003. Abstract 557c Moyle GJ et al. 15th IAC 2004. Abstract WePeB5725 f Huang et al. ICAAC 2002. Abstract 2040 clinicaloptions.com/hiv


Increasing Prevalence of X4- or R5/X4-Tropic Virus At Lower CD4+ CountsCCR5:

Pts with early-stage HIV disease tend to have pure R5-tropic virus

CXCR4:With advanced disease, X4- or dual-tropic virus emerges

Associated with more rapid clinical and immunologic progression

CCR5 inhibition could select for more virulent X4-tropic virus

Moyle G, et al. ICAAC 2004. Abstract 1135.

16 16 14.8

41.9 40

01020304050607080

> 300

248

Prev

alen

ce o

f X4

or R

5/X4

(%)

90100

201-300

104

101-200

81

51-100

31

< 50

50

CD4+ Cell Countn =

HIV-1

HIV-1 envelope

glycoprotein

TT--cell surfacecell surface

gp120

gp41

CCR5

CD4

gp120

gp41HIV-1

TT--cell surfacecell surface

CCR5

CD4

8

HIV Attachment andFusion Targets for InhibitionHIV Attachment andHIV Attachment andFusion Targets for InhibitionFusion Targets for Inhibition

Virus-CellFusion

VirusVirus--CellCellFusionFusion

Moore JP, et al. PNAS. 2003;100:10598-10602.

gp41gp41gp41

gp120gp120gp120

V3 loopV3 loopV3 loop

CD4Binding

CD4CD4BindingBinding

CD4CD4CD4

CellMembraneCellCellMembraneMembrane

CoreceptorBinding

CoreceptorCoreceptorBindingBinding

CCR5/CXCR4(R5/X4)

CCR5/CXCR4CCR5/CXCR4(R5/X4)(R5/X4)

CoreceptorAntagonistsUK-427,857GW-873140

SCH DAMD-070

CoreceptorCoreceptorAntagonistsAntagonistsUKUK--427,857427,857GWGW--873140873140

SCH DSCH DAMDAMD--070070

BMS-488043

TNX-355

BMS-488043

TNX-355

FuzeonFuzeonVirus

(CD4 Cell)

VirusVirus



HIV Entry Inhibitors

Possible Advantages

– Work early in virus life cycle

– Prevention or postexposure

– Lack of cross-resistance with existing drug classes

– Lack of “cellular resistance”

– Potential cellular targets

Possible Disadvantages– Targets (such as gp120)

may be highly variable

– Cellular targets: mechanism toxicity

– Mode of delivery (TANOX TNX 355, Fuzeon)

CCR5 Inhibitor UpdateCCR5 Inhibitor UpdateAplavirocAplaviroc (GW(GW873140)873140)-- GSKGSK

Phase II studies in naives (+Phase II studies in naives (+CombivirCombivir) and treatment experienced (+ OBT) ) and treatment experienced (+ OBT) stopped due to liver toxicitystopped due to liver toxicity

VicrivirocVicriviroc (SCH(SCH--417690)417690) –– ScheringSchering--PloughPloughPhase II study in naives (boosted Phase II study in naives (boosted qd+Combivirqd+Combivir vsvs Sustiva+CombivirSustiva+Combivir) )

stopped due to increased viral load in some patients. Treatment stopped due to increased viral load in some patients. Treatment experienced study (+OBT) completely enrolled by ACTG. We are waiexperienced study (+OBT) completely enrolled by ACTG. We are waiting ting for data.for data.

Concerns about potential increase in cancers.Concerns about potential increase in cancers.

MaravirocMaraviroc (UK(UK--427857)427857)-- PfizerPfizerBoth naBoth naïïve and treatment experienced studies ongoing. One case ve and treatment experienced studies ongoing. One case

of liver toxicity (1/1000 patients) in naof liver toxicity (1/1000 patients) in naïïve study that may have ve study that may have not been caused by the study drug. Lower dose arm stopped in not been caused by the study drug. Lower dose arm stopped in treatment natreatment naïïve study due to lack of efficacy. A separate study ve study due to lack of efficacy. A separate study looking at drug efficacy in dual tropics patients (R5/X4) is looking at drug efficacy in dual tropics patients (R5/X4) is completed.completed.



How Will We Use CCR5 Inhibitors?Initial therapy– PROs:

– Naive patients less likely to have X4- or R5/X4-tropic virus

– Well tolerated and convenient in early trials

– CONs:– Tough competition: 1 pill QD, well tolerated, minimal long-term toxicity

– May require tropism screening: more expensive if used upfront before initial therapy in all patients

– Increased virologic failure with vicriviroc vs EFV for initial therapy

– Which agent(s) would it replace? Or will they be “add-on”drugs only? We will know at the end of 2006



CCR5 InhibitorsAdvantages– One agent in phase II and

one in phase III

– Short-term activity clear

– Cross resistance may not be the “rule”

– Likely synergy with Fuzeon

Disadvantages– Not clear when these agents

will be available– Potency of vicriviroc may be

less than anticipated

– Optimal settings for use have not been defined

– Utility in pts with dual/mixed variants uncertain

– Longer-term toxicity still an open question

– May be tied to phenotype assay



Problems:– People who fail initial therapy

may have been non-adherent to the simplest of regimens

– The “first shot’ may always be the “best shot”

– Infection with resistant virus can eliminate many sequences

Sequencing Therapy in 2006 and Beyond: How Many Tries Do You Get?

Plausible scenarios:– 2 NRTIs + 1 NNRTI

– 3 NRTIs + 1 PI/r

– 1 PI/r + CCR5 inhibitor ± NRTIs

– Integrase inhibitor + PI/r+NRTI+Fuzeon

– Integrase inhibitor + Fuzeon + other CCR5 inhibitor ± PI/r

– Maturation inhibitor + other entry inhibitor(s) + ?

9

ResourcesResources11--800800--TRIALSTRIALS--A for studies in your areaA for studies in your areaClinicalTrials.govClinicalTrials.gov. Type key words . Type key words ““ HIV treatment HIV treatment experiencedexperienced”” in search box for all studiesin search box for all studiesSalvageTherapies.orgSalvageTherapies.org-- My web siteMy web siteNATAP.orgNATAP.org-- Complete conference reports and daily Complete conference reports and daily updatesupdatesACRIA.orgACRIA.org-- Another good directory of clinical trials Another good directory of clinical trials ClinicalOptions.comClinicalOptions.com-- for professionalsfor professionalsTAGTAG’’ss pipeline report pipeline report ((http://www.aidsinfonyc.org/tag/tx/antiretroviralsPipelineJuly05.http://www.aidsinfonyc.org/tag/tx/antiretroviralsPipelineJuly05.html)html)

Join Join ATACATAC’’ss Drug Development Committee (Drug Development Committee (www.atacwww.atac--usa.org)usa.org)-- Be an activist and be in controlBe an activist and be in controlJoin the largest discussion group in the internet by Join the largest discussion group in the internet by sending a blank email to sending a blank email to

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Inform Yourself of Your Options and Inform Yourself of Your Options and Never Give Up !Never Give Up !

Date post:	13-Jul-2020
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Emerging Therapies for HIV Multiple Drug · Autologous Delipidated HIV Therapeutic Vaccine Lipid...

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