Enfuvirtide (T-20)

Leroy Benons

Medical Advisor / HIV

Roche Products Ltd.

Contents of presentation

• Overview of T-20 development

• Summary of study results (Toro 1 and 2)

• Resistance

• Paediatric use

• Side effects - injection site reactions

• Access in the UK

• When to use T-20

• Development plans and T-1249

Overview of T-20 development

Discovery and Development of FUZEON

• Duke University– Dani Bolognesei and colleagues

– Looking for targets for HIV vaccines

• HR2 had antiviral properties

• Established TRIMERIS– independent Co, registered on the Stock Exchange

• Marketing of Fuzeon– Roche / Trimeris - North America

– Roche - ROW

FUZEON - Product description

• The FIRST of a completely new class of ARV for the treatment of HIV, the fusion inhibitors

• The first new class of ARV to be introduced since the protease inhibitors (PIs) in 1995.

• No direct competitors until 2006, but indirect competition from improvements in present / new agents

• 36 amino acid peptide (protein)

• Subcutaneous injection / BID / 90 mg - 2ml vial (abdomen, arm, thigh)

SAQUINAVIR

M.W. 767

ZIDOVUDINE

M.W. 267

O OOHNH

O ONH2NH

M.W. 4,492

aceuticals

FUZEON

The most complex molecule ever chemically synthesized ?

FUZEON

The most complex molecule ever chemically synthesized ?

Manufacturing Issues

• 106 steps (chemical reactions - PIs= 8-12 steps)

• 18 secondary suppliers (19 sources of raw materials)

• Complex (synthetic peptide)

• 45 Kg raw materials - 1 Kg of T-20

• Total peptide production 30 kg (worldwide)

• Need to produce 40000-70000 kg T20 /year to meet demand

Number of Annual Daily Product Amino Acids Production Dose

Calcitonin 32 10 kg 0.5 mg

Leuprolide 9 20 kg 5 mg

Fuzeon 36 3,000 - 5,000 kg 180 mg

Manufacturing Capacities of Peptide Drugs

Fuzeon - manufacturing Scale

AnnualProduction

Batch Size(T-20) Facility

Intended Use

2-5 Kg 0.2 - 0.3 Kg ToxicologyClinical

30 Kg 0.5 - 1 Kg Pilot PlantLaboratory

Clinical

80-90 Kg 3 - 4 Kg Pilot Plant Clinical

# of Patientsper year

Laboratory 30 - 70

1100 - 1200

3000-5000 Kg > 30 Kg FacilityUnder Construction

Commercial 40000 - 70000

RNARNA

ProteaseProtease

DNADNA

NucleusNucleus

Protease inhibitorsProtease inhibitorsReverse transcriptase inhibitorsReverse transcriptase inhibitors

FusionFusionInhibitorsInhibitors

Fusion InhibitonFusion Inhibiton

TTReverseReverse

transcriptasetranscriptase

Video on Mechanism of Action of FUZEON

Dosing and Administration of FUZEON

Dosage of FUZEON

• FUZEON is administered bid (usually the morning and evening) as a subcutaneous injection.

• Each dose consists of 1.0 mL injection containing 90 mg of FUZEON delivered with a 1 mL NMT Safety Syringe.

Preparation of FUZEON

• FUZEON is supplied as a lyophilized powder, which must be reconstituted in water for injection.

• All of the necessary components needed for FUZEON injection are supplied in a kit.

Dosing and Administration of FUZEON The kit

The FUZEON kit contains the following five components:

• 60 vials of FUZEON

• 60 vials of water for injection

• Alcohol pads

• 60 - 3 mL NMT Safety Syringe

• 60 - 1 mL NMT Safety Syringe

Dosing and Administration of FUZEON

• The 3 mL NMT Safety Syringe is used for sterile water; the 1 mL NMT Safety Syringe is used for injecting the FUZEON solution

• FUZEON typically requires 10 to 20 minutes to dissolve in sterile water, but may take up to 45 minutes

• The injection site should be rotated and should not include the area around the navel, the belt line, or any area where there is an ongoing injection site reaction

Convenience Box 358 x 177 x 202.8mm

Convenience Box "top view"

Convenience Box "overview"

Efficacy of FUZEON - The Clinical Trials

T-20 clinical synopsis

Phase I/II TRI-001 Proof of concept

Phase II

TRI-003 Outpatient dosage form

T20-204 Paediatric study

T20-205 Chronic safety

T20-206 Dose comparison

T20-208 Formulation improvements

PivotalT20-301Phase III

T20-302 Pivotal

T20-305 Safety study

n = 17

n = 73

n = 14

n = 70

n = 71

n = 46

Up to = 450

n =491

T20-310 Paediatric study n = 48

TORO Studies

What is an ‘Individualised / Optimizedbackground’?

A combination of antiretrovirals, carefully selected to provide the maximum antiretroviral activity amongst the available options, used in conjunction with a new agent as part of an antiretroviral regimen.

New agent

Drug E

Available options

Drug A

Drug B

Drug C

Drug D

Individualized background

SELECTED FOR MAXIMUM ACTIVITY

Drug A Drug C

Individualised / Optimized Background

• Regimens are individualized through selection of maximally active drugs determined by prior treatment history and, wherever possible, HIV resistance testing

• Other considerations may include the use of pharmacokinetic enhancement and, for patients with few remaining options, attempts to limit HIV replicative capacity

Individualized background

SELECTED FOR MAXIMUM ACTIVITY

Treatment history

Resistance test

information

TORO-2 Study

Pivotal Studies: 24 week primary analyses TORO 1: (US, Canada, Mexico, Brazil) & TORO 2: (Europe, Australia)• Population:

– Prior experience to 1 NRTI, 1 NNRTI and 1-2 PIs

3-6 months experience on each class or documented viral resistance

– HIV RNA 5000 copies/mL

• Design:– Open Label, Randomized Multi-Center, International

• Treatments (Planned N=525 each, randomized 1:2):

– Optimized Background [OB, 3-5 antiretrovirals (ARVs) based on history, viral GT/PT] (n=175)

– Fuzeon (ENF, T-20: 90 mg sc bid) + OB, (n=350)

ENF+OB OB Total (N=335) (N=169) (N=504)

Baseline RNA 5.1 5.1 5.1(median, log10)

Baseline CD4+ cell count 98 102 98(median, cells/mm3)

Prior ARVs (median) 12 12 12

Years ARV use (median) 7.4 7.4 7.4

Prior ADEs (N, %) 250 (75%) 138 (82%) 388 (77%)

PSS at entry (mean) 1.4 1.4 1.4

PSS = Number of drugs in OB regimen to which virus was phenotypically sensitive

TORO 2:Demographics and Baseline Characteristics

Gender, race and age were balanced across treatments

TORO 2: Summary of AEs Related to any drug in Original Regimen prior to switch(> 5% through Wk 24, excluding ISRs)

Adverse Event FUZEON + OB OB(N=335) (N=169)

Total Patients with at least one related AE 241 (71.5%) 114 (67.5%)

Diarrhea 67 (19.9%) 34 (20.1%)

Nausea 38 (11.3%) 25 (14.8%)

Fatigue 29 (8.6%) 11 (6.5%)

Vomiting 25 (7.4%) 14 (8.3%)

Dermatitis 26 (7.7%) 7 (4.1%)

Asthenia 24 (7.1%) 7 (4.1%)

Headache 20 (5.9%) 13 (7.7%)

Insomnia 19 (5.6%) 10 (5.9%)

Pyrexia 19 (5.6%) 9 (5.3%)

Depression 18 (5.3%) 4 (2.4%)

Pruritus 17 (5.0%) 5 (3.0%)

Peripheral Neuropathy 17 (5.0%) 9 (5.3%)

TORO 2: Primary Study Endpoint HIV-1 RNA Log Change from BL at Week 24

(Delta=0.78, P<0.0001)

Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)

OB aloneFUZEON+ OB

N=169N=335

TORO 2: Secondary Analysis Response at Week 24 (ITT, DC=Failure)

1 log decreasefrom BL

< 400 copies/mL

< 50 copies/mL

FUZEON + OB OB

P<0.0001

P=0.0099

2 visits required to confirm viral load response

TORO 2:Secondary Analysis Mean CD4+ Cell Count Change from BL at Week 24

P=0.023

Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)

OB aloneFUZEON + OB

TORO 2: Conclusions

• Safety:

– ISRs occur in almost all patients (only treatment limiting in 3%)

– Other AEs comparable across treatments

• Primary study endpoint:

– plasma HIV-1 RNA analysis statistically significant favouring the Fuzeon arm

• Secondary endpoints:

– Responder analyses (1 log drop, <400, <50 c/mL) statistically significant favouring the Fuzeon arm

– CD4 cell count change from baseline statistically significant favouring the Fuzeon arm

TORO 1 / TORO 2 Conclusions

• Patient Populations:

– BL RNA (median): 5.2 - 5.1 log10 copies/mL

– CD4 (median): 80 - 98 cells/mm3

– PSS (mean) 1.7 - 1.4

• Primary Efficacy ENF + OB vs. OB:

– TORO 1: -1.7 vs. -0.76; Delta = 0.93; p<0.0001

– TORO 2: -1.43 vs. -0.65; Delta = 0.78; p<0.0001

– Sensitivity analyses and analysis of secondary virologic and immunologic endpoints consistently demonstrated benefit of ENF+OB over OB

• Safety

– ISRs occur in almost all patients; treatment limiting in 3%

TORO 1 / 2:Conclusions

• Fuzeon, the most clinically advanced fusion inhibitor, was studied in two separate multinational studies in a total of approximately 1000 heavily pretreated patients.

– Injection site reactions were the most common AE; treatment limiting in only 3%

– Significant benefit in primary and secondary virological endpoints as compared to OB alone.

– Significant immunologic benefit as compared to OB alone.

• Results consistent across both studies

TORO 2 (Sub-group Analyses)

TORO 2: Demographic subpopulations: Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population)

0Male Female White Non-White

< 40 years

= 40 years

Least Squared Means Log Change from Baseline (LOCF) - Intent-to-Treat Population

** ****

N=43N=316

**p p < 0.05< 0.05

Gender Race Age

ENF + OBOB

TORO 2: Baseline viral load and CD4:Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population)

< 40,000copies/mL

= 40,000copies/mL

< 100 CD4cells/mm

= 100 CD4cells/mm

**** **

**p p < 0.05< 0.05

ENF + OBENF + OBOBOB

TORO 2: Baseline GSS score:Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population)

GSS 0 GSS 1 GSS 2 GSS 3 GSS 4 GSS =5

N=104N=49

N=45N=33

**p p < 0.05< 0.05

ENF + OBOB

TORO 2: Baseline PSS score:Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population)

PSS 0 PSS 1 PSS 2 PSS 3 PSS 4 PSS =5

ENF + OBOB

N=69 N=43 N=21

**p p < 0.05< 0.05

N=4N=101

TORO 2: Multiple regression analyses: Change from baseline to week 24 in log10 HIV-1 RNA data (LOCF): ITT

Predictor Estimate 95% C.I. p-value

Treatment with ENF -0.80 -1.01, -0.60 <0.0001

Baseline VL (per log10 copies/mL) -0.30 -0.47, -0.12 0.0009

Baseline CD4 count -0.21 -0.28, -0.14 <0.0001(per 100 cells/mm3)

PSS§ -0.19 -0.26, -0.11 <0.0001

Total adherence score* (per 10%) -0.11 -0.19, -0.04 0.0038

Prior LPV/r experience 0.86 0.65, 1.07 <0.0001

§ Replacing PSS with GSS gives similar results* Adherence based on 4 day recall

TORO 2: Conclusions

• Primary and secondary categorical analyses all favoured enfuvirtide and were consistent across TORO 1 and TORO 2

• Enfuvirtide demonstrated benefit across subgroups evaluated

• The enfuvirtide effect on viral load was seen across a range of PSS and GSS scores

TORO 2: Conclusions

Predictors of response included:

• Treatment with enfuvirtide

• Baseline viral load

• Baseline CD4 count

• PSS/GSS

• Adherence

• Prior LPV/r use (predicted poorer response)

Activities of Daily Living SurveyTORO 1 and 2

Patient acceptance of subcutaneous self-injections (Activities of Daily Living Survey)

• SIS survey (18-item psychometric questionnaire)– psychometric properties evaluated and found to be reliable in

assessing of self-injecting in trials

• n=661 (Toro 1 + 2)

• Evaluated patients experience with preparing and injecting

• Administered at 8 and 24 weeks (prior to seeing clinician)

0 20 40 60 80 100

Patient Responses (%)

Very easy or Easy Neutral Difficult Very difficult

Giving yourself injections

Keeping medication refrigerated

Dissolving medication in water

Disposing of needles and vials

Toro 1 & 2 - Activities of Daily Living (SIS Survey)

Green et al., Poster, HIV6, Glasgow

Not at all or a little Moderately Quite a bit Extremely

Patient Responses (%)

0 20 40 60 80 100

68.6%Traveling away from home

77.5%Being intimate or having sexual relations with a partner

70.1%Maintaining privacy about your health

77.8%Participating in recreational activities/sports

84.2%Socializing (or interacting) with family or friends

84.7%Working at a job or attending school

89.2%Getting around locally

Sleeping

Toro 1 & 2 - Activities of Daily Living

Patient acceptance of SC self-injections Conclusions

• In the Phase III trials, TORO 1 and TORO 2, patient acceptance of self-injections of FUZEON remained high over the 24 week treatment period.

• Most patients reported that self-injections were easy to administer and that injections had ‘little’ or ‘no impact’ on their daily routines.

• This should allow good treatment compliance, helping to ensure successful therapy.

• Additional analyses are planned once the 48-week data is available.

Injection Site Reactions (ISR)

Picture of Injecting Site Reactions (ISR)

ISR and related variables

• Severity of local ISRs is not dose related in the range used in

adults.

• Grade 3 & 4 ISRs were comparable in patients with and

without fat redistribution.

• Trend towards more frequent grade 3 signs/symptoms with

low BMI.

• Incidence of Grade 3/4 ISRs was not increased in patients

with a higher CD4 cell count.

ISRs - Drug-demographic interactions

• Demographic Subpopulations:– Gender (male or female)– Race (white or non-white)– Age (<40yrs or 40yrs)– Gp41 Antibody

• No apparent differences seen for subpopulations on:– Incidence– Most common symptom & signs– Severity of symptom & signs– Severity with duration of treatment– Duration of lesions– No. of lesions at any given visit

ISR discontinuation rate remains low & similar from week 24 to safety updatecut-off (week 48)

• Low ISR discontinuation rate and high adherence to treatment despite high overall incidence of ISR

• Week 24: 3% of patients discontinued due to ISRs

• Safety update: 4% of patients discontinued due to ISRs (majority patients reached Week 48)

Possible reasons for low discontinuation rate and high adherence to treatment despite high incidence of ISRs

• Motivated patients: heavily experienced

– Median duration of prior therapy: 7 years

– Median number of ARVs: 12

– Mean PSS: 1.6

• ISRs mostly mild to moderate in intensity

• While rate of ISR remain stable overtime, no apparent increase in severity overtime

ENF is the predominant factor for eliciting ISRs

• Animal studies suggest some role of vehicle, but a major contribution of enfuvirtide.

• Cannot be evaluated clinically (no placebo-control)

• Conclusions limited by:

– repeated injections in animals vs. “single” injections in humans

– placebo is not ideally matched (hypo-osmotic)

– uncertain relevance of animal findings to humans.

Pathological characterization of injection site changes in animals

• Gross (visible) changes:

– swelling, hardening, discoloration

• Microscopic changes:

– mixed inflammatory infiltrate (primarily macrophages, lymphocytes, eosinophils)

– nonspecific changes of hemorrhage, edema

– repeated injections of high concentrations resulted in granulomatous reaction (foreign-body type?)

No data currently available for guidance with medical management of local ISRs

• Anecdotal reports:

– massaging injection site or applying ice helpful in adult patients

– proper injection technique reduce severity/frequency

• Pediatric patients: optional use of topical anesthetic

– however, effect of topical anesthetic use not prospectively studied

• Three ongoing studies may assist in determining appropriate measures to prevent and/or treat ISRs

– Intervention study (T20-305): massage, topical steroids, heat, self injected vs. partner injected

– Clinical, histological, and immunochemical characteristics of ISRs at various times after the injection of ENF (T20-306)

– Injection site pathology study (NV16471)

FUZEON and RESISTANCE

Resistance testing

Drug resistant HIV can be identified by two in vitro methods;

• Genotyping and

• Phenotyping

Genotypic Resistance - 1

• Fuzeon

– a completely new class of ARV

– a unique MoA

• Mutations in the target enzymes of protease and the reverse transcriptase cause no reduction in susceptibility to T-20

• Baseline resistance to T-20 is rare.

Genotypic resistance - 2

• In vitro resistance:

– HIV- 1 isolates with substitutions in amino acids (aa) 36– 38 of the gp41 ectodomain correlated with varying levels of reduced FUZEON susceptibility in HIV site-directed mutants.

• In vivo resistance:

– Treatment- emergent substitutions in aa 36– 45 of gp41 HR 1 region have been observed in viruses from patients receiving FUZEON in Phase II and Phase III clinical studies. The substitutions observed in decreasing frequency were at amino acid positions 38, 43, 36, 40, 42 and 45.

Genotypic resistance - 3

• In Phase 11 studies (T20-205, 206 and 208) the most common substitutions in plasma virus on treatment were as follows;

– V38A (n=18)

– G36D (n=15)

– G36S (n=11)

– N43D (n=10)

– N42T (n=5)

• At the time of protocol defined virological failure, viruses from a total of 31/40 (78%) patients showed substitutions in gp41 aa 36-45.

Resistance testing - Phenotype

Antiviral EC50 values are dependent upon the assay type/protocol

DATA FOR WT (PRE-TREATMENT) HIV

• Using a cMAGI cell assay the geo mean EC50 was 0.016 g/ml (n=130)

• Using a JC53-BL cell assay mean EC50 was 0.16 g/ml (n=35) (Derdeyn et al)

• Using a PhenoSense Assay the mean EC50 was 0.26 g/ml (n=612)

• All are valid assays

Enfuvirtide susceptibility of isolates from Phase II clinical studies

GM+2SD=0.218 µg/mL

Geometric Mean (GM) EC50 = 0.020 µg/mL

The relationship between in vitro susceptibility and in vivo activity has not been established

T20-301+T20-302Histogram of Baseline EC50 (µg/mL)

0.01 0.02 0.03 0.07 0.16 0.34 0.73 1.59 3.45 7.48

EC50 (µg/mL)

GM+2SD=1.956 µg/mL

Geometric Mean (GM) EC50 = 0.259 µg/mL

Patients carrying the least sensitive virus pre-treatment respond similarly to FUZEONtreatment

• Patients carrying viruses with an EC50 value > (mean + 2SD) respond comparably to the total treated population in terms of reduction in viral load (HIV plasma RNA)

Fold-change in ENF susceptibility at virological failure through week 24

159 (77.2%)82 (72.6%)77 (82.8%)Greater than 10- fold

28 (13.6%)17 (15.0%)11 (11.8%)4 to 10- fold

19 (9.2%)14 (12.4%)5 (5.4%)< 4-fold

OverallT20-302T20-301

PHENOTYPIC CHANGES IN VIRUSES EMERGING WITHSINGLE T-20 RESISTANCE MUTATIONS: PHASE 2 STUDIES

Poster 22 : Seville, 2002

PHENOTYPIC CHANGES IN VIRUSES EMERGING WITHDOUBLE T-20 RESISTANCE MUTATIONS: PHASE 2 STUDIES

Poster 22; Seville 2002

FUZEON treatment emergent substitutionsin gp41 aa 36-45 in virological failure patients

• Of the patients who met virological failure, 94% carried virus with ENF-associated substitutions

• The most common substitutions were

– V38A, N43D, Q40H, G36D

• These mutations are associated with diminished

– ENF sensitivity in vitro

– replicative capacity in vitro

The high incidence of resistance to FUZEON at VF reflects the lack of sensitivityto the OB regimen

• 43.5% of patients had a PSS of 0

• 38.5% of patients had a PSS of 1 or 2

• A large proportion of patients were essentially treated with ENF as monotherapy

Failure rates for FUZEON+OB vs. OB only through week 24

FUZEON + OB OBScore at No. No. No. No.Baseline Pts Failed (%) Pts Failed (%)

PSS0 191 131 (68.6%) 99 94 (94.9%)1-2 288 116 (40.3%) 148 103 (69.6%)3-4 144 40 (27.8%) 73 33 (45.2%)5 21 7 (33.3%) 10 4 (40.0%)

GSS0 112 82 (73.2%) 53 52 (98.1%)1-2 368 159 (43.2%) 188 133 (70.7%)3-4 152 49 (32.2%) 82 46 (56.1%)5 18 6 (33.3%) 8 4 (50.0%)

Viruses with aa36-45 resistance mutations are less fit than wild-type

• Wild-type virus outgrows mutants in in vitro grow competition

• Mutants are outgrown by wild-type in vivo on cessation of FUZEON therapy

FUZEON-resistance mutations are not seen in pre-treatment HIV

• There is a low incidence of variants in aa 36-45 of pre-treatment HIV gp41

– these are not resistance mutations in in vitro assays

• Patients carrying viruses with pre-treatment variants or wild-type respond equally to FUZEON treatment in terms of VF

• Viruses carrying the most common pre-treatment variant, N42S, are slightly more sensitive to FUZEON in vitro

Resistance summary

• Unique virus target and mode of action

• No cross resistance with approved ARVs

• Active against

– Multidrug-resistant isolates

– CCR5, CXCR4, and dual tropic isolates

• Pre-existing resistance to ENF is rare

• Specific substitutions in gp41 aa 36-45

– are associated with reduced susceptibility to FUZEON in vitro

– are associated with diminished in vitro replicative capacity

Paediatrics

Paediatric Question

• Roche acknowledges that there is a medical need for alternative ART also in children.

– To summarise the available clinical data in children and provide an outline of ongoing and planned paediatric trials

– To discuss if a dose recommendation for children of 6 years and older can be supported by available data

– To discuss the need for a specific paediatric formulation or presentation that would facilitate flexible and accurate dosing of enfuvirtide in children

Current and future paediatric clinical program

48 weeks+ extension/ ongoing

40/482.0 mg/kg up to 90 mg deliverable SC BID

Treatment experiencedHIV RNA5,000 c/mlAge 3-16 yrs

T20-310/NV16056

96 weeks/ completed

Part A 12/12Part B 14/12

Part A (single dose, IV & SC): 15, 30 , 60 mg/m2 Part B (chronic dosing): 30, 60 mg/m2 SC BID

Treatment experiencedHIV RNA>10,000 c/mlAge 3-12 yrs

T20-204/ P1005**

Duration/ Status

Enrolled*/ Planned

TreatmentPopulationStudy

* As of March 2003**Conducted by Pediatric AIDS Clinical Trials Group (PACTG)

Current and future paediatric clinical program

2 weeks/ planned

0/16-202.0 mg/kgTreatment experiencedHIV RNA5,000 c/mlAge 6 mos - 6 yrs

Infant/children study

Until commercial availability/ ongoing

9/502.0 mg/kg up 90 mg deliverable SC BID

Treatment experiencedHIV RNA >10,000 c/mlAge 6-16 yrs

T20-305

48 weeks+ extension/ ongoing

40/482.0 mg/kg up to 90 mg deliverable SC BID

Treatment experiencedHIV RNA5,000 c/mlAge 3-16 yrs

T20-310/NV16056

96 weeks/ completed

Part A 12/12Part B 14/12

Part A (single dose, IV & SC): 15, 30 , 60 mg/m2 Part B (chronic dosing): 30, 60 mg/m2 SC BID

Treatment experiencedHIV RNA>10,000 c/mlAge 3-12 yrs

T20-204/ P1005**

Duration/ Status

Enrolled*/ Planned

TreatmentPopulationStudy

* As of March 2003**Conducted by Pediatric AIDS Clinical Trials Group (PACTG)

Paediatric data currently available (Nov 02 safety update)

• Patient– 47 paediatric pts included

• 35 patients aged 6–16 yrs

• Exposure – 35 paediatric patients 6–16 years of age with duration of ENF

exposure ranging from 1 dose to 48 weeks

• 30 patients 6yrs with exposure to at least 24 weeks

– 10 patients 6yrs with exposure to at least 48 weeks

• Pharmacokinetic– 32 paediatric patients 3–16 years

• 20 patients 6–16 years

• Based on a limited number of patients:

– ENF was well tolerated with comparable safety profile to adults

– Most common AEs were mild-to-moderate injection site reactions (ISRs)

– Two related SAEs

• Cellulitis and ISR

Dose recommendation for patients 6 – 16 yrs: safety (2mg/kg BID dose)

Dose recommendation for patients 6 – 16 yrs: (2mg/kg BID dose)

Cross-study comparison

T20-206 N=16 Paediatric P1005 N=12

1 log decrease from BL

<400 copies/ml <50 copies/ml

Double- or triple-class experienced

Double-class experienced

Alternative dosage forms

• Current adult formulation allows for dosing in children and is being used in ongoing paediatric trials

• Roche is exploring the potential for alternative dosage forms which may also allow flexible dosing in children

Conclusion

• Given the need for alternative ART in children, enfuvirtide at a 2mg/kg BID dose in children 6 to 16 years of age is supported by the available clinical data

Access in the UK

Early Access Programme (IPS)

• EAP - small and short lived

• From November 2002 - March 03 ( extended to May 2003)

• Europe and RoW - 600 patient slots

– allocated based on HIV prevalence (WHO)

– 43 patient slots in UK (37 used to date)

• EAP with free drug (no hidden costs)

EAP (IPS): Global criteria

• Male and female HIV-1 infected adults or adolescents

( 16 years of age)

• CD4 lymphocyte count 100 cells/mm3 and HIV-1 RNA

viral load > 10,000 copies/mL while on HAART (latest

available measurement must be within the last 90 days)

• Also:

– Patients should have prior documented genotypic and / or phenotypic resistance and /or;

– At least 6 months exposure to all 3 current classes of antiretrovirals and /or

– Treatment limiting toxicity

FUZEONIPS- Status (22nd April 03) - Location of patients

• London (20)• Royal London (1)

• UCL (3)

• St Mary’s (3)

• Chelsea & Westminster (7)

• London and Barts (3)

• St Thomas’ (1)

• Kings (1)

• Outside London (17)

Regulatory Timelines Update

• Status

– USA

• Approval received March 03

• EU

– Expedited review

– Positive Opinion (20 March 03)

– Approval expected end-April 03

• UK

– Stock receipt (4-6 weeks after approval)

– Launch end-May 03

When to use enfuvirtide ?

• Not too early– after failure of NNRTI and PI (3rd line)

– patient with tolerability problems to Nukes or PIs

– optimal response with 2 other active drugs

• Not too late– need active agents to construct OB

– avoid functional monotherapy

Development plans and T-1249

Designed 39-amino acid synthetic peptide Binds to a slightly different sequence of gp41 than ENF

Maintains antiretroviral activity against most isolates with

reduced susceptibility to ENF in vitro Demonstrates potent short term antiviral activity in most

patients failing an ENF-containing regimen Further studies will evaluate efficacy and safety in this

patient population

T-1249

HR1 cc HR2FPNH2 COOHtm

ENFT-1249

T-1249 Demonstrates Potent Antiviral Activity over 10 Day Dosing in Most Patients who Have Failed a Regimen Containing Enfuvirtide (ENF):

Planned Interim Analysis of T1249-102, a Phase I/II Study

GD Miralles1*, J Lalezari2, N Bellos3, G Richmond4, Y Zhang1, H Murchison1, B Spence1, C Raskino5 and

R DeMasi1 for the T1249-102 Study Group

1Trimeris, Inc., Durham, 2Quest Research, San Francisco, CA; 3Southwest ID, Dallas, TX; 4Ft. Lauderdale, FL; 5Roche, Welwyn, U.K.

Objective

To evaluate the safety and short term activity of T-1249 on ENF resistant isolates in vivo

Design

Ten day add on therapy where T-1249 at a dose of 192 mg/daily replaces ENF in a failing regimen

Entry Criteria: Stable ENF-containing ARV regimen for the past 8 weeks. Two most recent viral loads of 5,000 and 500,000 copies/mL (with protocol defined VF)

Patients are permitted to dose 192 mg QD or 96 mg BID

Sample Size of 50 Patients

T1249-102

T1249-102 Study Design

Stable antiretroviral background

ENF with VL 5,000T-1249 192 mg

x 10 days

Stop ENFDay 5 Day 8 Day 11

Viral Load taken at BL and each Study visitGT and PT performed at BL (Day 1) and at Day 11

BL (Day 1)Start T-1249

T1249-102Baseline Patient Characteristics: Planned Interim analysis

Treated Population (25 patients)

22 (88%) Males; 3 (12%) Females; Mean age 42 years

Median exposure to ENF: 70.1 weeks (range 38.1 - 176.0)

Median Time from ENF Failure (n=25): 59.9 weeks (range 28.3-136.0)

Median baseline HIV RNA: 5.0 log10 copies/mL (range 3.8-5.5)

6 (24%) subjects enrolled from ENF Phase II studies

19 (76%) subjects enrolled from TORO 1

T1249-102Patient Disposition

All 25 patients completed 10-day dosing

After completion of T-1249 dosing, one patient with advanced COPD died on Day 11 from pneumonia resulting in respiratory failure

T1249-102Baseline Resistance TestingPlanned Interim Analysis

At baseline, 23 patients had both GT and PT, 1 patient had GT only, and 1 patient had neither. 24/25 (96%) had Baseline GT or PT results (ITT population).

All 24 patients demonstrated GT substitutions associated with ENF-resistance.

The GM change in ENF susceptibility between BL in TORO 1 and BL in T1249-102 was 77-fold compared with a 2-fold GM change for T-1249 susceptibility (n=15)

T1249-102Treatment-Emergent Serious Adverse Events (SAE)

Possible Allergic Reaction: AE of rash (Grade 2) associated with fever observed in one patient after completion of dosing (night of Day 11). Resolved without treatment in 48 hours.

* Safety Population (SAP): n=25

Five SAEs reported in three patients 3 (12% SAP*)

Patient # Preferred Term N (%) Related T-1249

200764 Alanine aminotransferase (ALT) 1 (4%) NoincreasedAspartate aminotransferase (AST) 1 (4%) Noincreased

202730 Bronchitis acute NOS 1 (4%) No200148 Pneumonia 1 (4%) No

Respiratory failure 1 (4%) No

T1249-102Incidence TE Grade 3 & 4 Laboratory Toxicities (reported by n=3 patients {12%})

* All reported from the same patient prior to demise with multiorgan failure

Laboratory Events Grade 3 Grade 4 Total

N (%) N (%) N (%)

Chemistry

ALT 0 1 (4%) 1 (4%)

AST 0 1 (4%) 1 (4%)

Calcium 0 1 (4%)* 1 (4%)

Creatinine 1 (4%)* 0 1 (4%)

Glucose 1 (4%)* 0 1 (4%)

Hematology

ABS Neutrophils 1 (4%) 0 1 (4%)

T1249-102 Log10 HIV RNA Mean and Median Change from Baseline (ITT)

0 5 8 11Study Day

BL Day 11

Median -1.12 (CI -1.50; -0.83)

N=24 22 24 24

Percent of patients with 1 log10 drop in HIV RNA according to length of ENF therapy after VF

7/7 8/17

24-48 wk > 48 wk

Median drop -1.6

Median drop -0.94

Percent of patients with 1 log drop

5 8 11

Study Day

T1249-102 Percent of patients with 1.0 log Decline (ITT*)

* Missing=Failure

T1249-102 Conclusions Interim analysis First 25 patients

T-1249 demonstrates potent short term antiviral activity in most patients failing an ENF-containing regimen.

The time on ENF following virological failure inversely correlates with short-term antiviral responses to T-1249

The safety and efficacy of T-1249 remains to be tested in clinical trials during chronic administration.

The results from this study demonstrate that fusion inhibitors constitute an expanding class of antiretroviral agents with the potential to be sequenced

Timelines

• Phase II trials will start in late 2003

• Followed by Phase 111 trials

• Hope to launch in 2006

BACK -UPS

Mechanism of Action

Representation of the HIV binding process

Working model of HIV fusion

Representation of gp41 showing the HR1 and HR2 region

Working model of HIV fusion inhibition

How do we interpret resistance tests?One possible approach:

• Resistance does not always have a binary classification (ie: ‘fully sensitive’ or ‘fully resistant’). PSS and GSS may not be integer

• New regimens are selected to give maximal PSS or GSS

• A PSS or GSS of at least 2 may be needed for durable suppression

• A PSS or GSS >2 is preferable if possible

PSS: Phenotypic sensitivity score

GSS: Genotypic sensitivity score

The number of drugs in a

regimen to which a patient’s

virus is considered

sensitive by phenotyping

Phenotypic resistance

determined by reference to

‘cut-off’ thresholds of

fold-resistance

The number of drugs in a

regimen to which a patient’s

virus is considered

sensitive by genotyping

Genotypic resistance

determined by mutation

analysis algorithms

Phenotypic cut-offs used in resistance testing

TECHNICAL BIOLOGICAL CLINICAL

• Based on assay reproducibility

• Not drug-specific

• Being superceded by biological and clinical cut-offs

• Based on upper limit of susceptibility range observed in panel of wild-type isolates

• Drug specific

• Based on direct fold change/ response correlation from clinical studies

A test may give only a partial answer to drug sensitivity

THEREFORE

Resistance tests must be performed on therapy

Prior resistance test results and/or full clinical history must be factored in to new drug selection

Low fitness of resistant strains

Patient stops drugs

Reversion to wild type

• Undetectable minority populations remain

• HIV sanctuary sites in body compartments

• Latently infected CD4 cells

Cause resistance to

‘ARCHIVE’

RECHALLENGE RE-EMERGENCE

TORO- 1 Study

Fuzeon (ENF, T-20) in Combination with an Optimized Background (OB) Regimen vs. OB

Alone in Patients with Prior Experience or Resistance to Each of the Three Classes of

Approved Antiretrovirals (ARVs) in North America

and Brazil (TORO 1)

K. Henry, J. Lalezari, M. O'Hearn, B. Trottier,J. Montaner, P. Piliero, S. Walmsley, J. Chung,

L. Fang, J. Delehanty, M. Salgo on behalf of the

TORO 1 study group.

TORO 1: Demographics and Baseline Characteristics

ENF+OB OB Total (N=326) (N=165) (N=491)

Baseline RNA 5.2 5.2 5.2(median, log10)

Baseline CD4+ cell count 76 87 80(median, cells/mm3)

Prior ARVs (median) 12 12 12

Years ARV use (median) 7.0 7.1 7.0

Prior ADEs (N, %) 273 (84%) 148 (90%) 421 (86%)

PSS at entry (mean) 1.7 1.8 1.7

PSS = Number of drugs in OB regimen to which virus was phenotypically sensitive

Gender, race and age were balanced across treatments

TORO 1:Patient Disposition (ITT)

ENF+OB(N=326)

OB(N=165)

Remain on OriginalRandomized Treatment

VF, Switch OBto ENF + OB

Non-VF(N=190)

VF(N=136)

Total(N=326)

Non-VF

(N=59)

VF, NoSwitch(N=25)

Total(N=84) (N=81)

No. Discontinued 20 17 37(11.3%)

8 10 18(21.4%)

6(7.4%)

5 5 10 (11.9%)Safety AE/Lab

16 (4.9%)

9 (2.8%) Not applicable

2 (2.5%)

1 (1.2%)

Non-Safety Admin/Other Failure to return Insuff ther resp. Refused Trt

Discontinuations: ENF + OB 11.3%, OB 21.4% For further details see poster LbOr19b

TORO 1: Summary of AEs Related to any drug on Original treatment prior to switch(> 5% on ENF + OB, through Wk 24, Excluding ISRs)

Adverse Event ENF + OB OB(N=326) (N=165)

Total Patients with at least one related AE 253 (77.6%) 123 (74.5%)

Diarrhea 79 (24.2%) 63 (38.2%)

Nausea 72 (22.1%) 48 (29.1%)

Fatigue 64 (19.6%) 28 (17.0%)

Peripheral Neuropathy 36 (11.0%) 9 (5.5%)

Insomnia 32 (9.8%) 10 (6.1%)

Headache 29 (8.9%) 15 (9.1%)

Appetite Decreased 26 (8.0%) 5 (3.0%)

Vomiting 25 (7.7%) 21 (12.7%)

Dizziness (Excl. Vertigo) 24 (7.4%) 7 (4.2%)

Weight Decreased 18 (5.5%) 6 (3.6%)

Flatulence 17 (5.2%) 13 (7.9%)

TORO 1: Primary Study Endpoint HIV-1 RNA Log Change from Baseline at Week 24

(Delta=0.93, P<0.0001)

Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)

OB aloneFuzeon + OB

N=165N=326

TORO 1: Secondary Analysis Response at Week 24 (ITT, DC=Failure)

1 log decrease from BL

< 400 copies/mL

< 50 copies/mL

Fuzeon + OB OB

P<0.0001

P=0.0002

2 visits required to confirm viral load response2 visits required to confirm viral load response

TORO 1: Time to Virological Failure

Study Week

ENF+OB

0 4 8 12 16 20 24

P<0.0001

Time to protocol definedVF starts at week 6*

* For definition of virologic failure, see Back-up slide

TORO 1: CD4+ Cell Count Change from Baseline at Week 24

P=0.0001

Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)

OB aloneFuzeon + OB

TORO 1: Conclusions

• Safety:

– ISRs occur in almost all patients (only treatment limiting in 3%)

• Primary study endpoint:

– plasma HIV-1 RNA analysis statistically significant favoring the Fuzeon arm

• Secondary endpoints:

– Responder analyses (1 log drop, <400, <50 c/mL) statistically significant favoring the Fuzeon arm

– CD4 cell count change from baseline statistically significant favoring the Fuzeon arm

TORO 2:Patient Disposition (ITT)

ENF+OB(N=335)

OB(N=169)

Remain on OriginalRandomized Treatment

VF, Switch,OB to ENF +

OBNon-VF(N=170)

VF(N=165)

Total(N=335)

Non-VF(N=39)

VF(N=16)

Total(N=55) (N=114)

No. Discontinued 23 34 57(17.0%)

2 6 8(14.7%)

9(7.9%)

1 1 2 (3.6%)Safety AE/Lab/Death

23 (6.9%)

11 (3.3%) Not Applicable

4 (3.5%)

3 (2.6%)Non-Safety Admin/Other Insuff ther resp. Refused Trt

Discontinuations: ENF + OB 17.0%, OB 14.7% For further details see poster LbOr19a

ISR Severity rating scale in the T20-208 Study

Parameter Grade 1 Grade 2 Grade 3 Grade 4* (Mild) (Moderate) (Severe) (Potentially

Life-threatening)

Erythema:diameter (mm) <25 mm >25 mm >50 mm >85 of skin redness (size of a but <50 mm but <85 mm at the site quarter) of injection

Induration:diameter (mm) Slight present but <25 >25 mm >50 mm of palpable but <50 mm hardness of the skin at the site of injection

Pain:subjective Mild tenderness Moderate pain Severe pain Severe pain report at injection site without limitation requiring analgesics requiring

of usual activities and/or limiting usual narcotic analgesics

or not respondingto analgesics

*Grade 4 local reactions require a clinic visit within 12 to 24 hours of the event

Enfuvirtide (T-20)

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Revista T. A nº 20