Enfuvirtide T20

1
Enfuvirtide (T-20)

• Leroy Benons
• Medical Advisor / HIV
• Roche Products Ltd.

2
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

3
Overview of T-20 development
4
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

5
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)

6
?
FUZEON The most complex molecule ever chemically
synthesized ?

Pharmaceuticals
T-20 M.W. 4,492
SAQUINAVIR M.W. 767
ZIDOVUDINE M.W. 267
7
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

8
Manufacturing Capacities of Peptide Drugs
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
Capacity being created
9
Fuzeon - manufacturing Scale
of Patients per year
Annual
Batch Size
Intended Use
Production
(T-20)
Facility
30 - 70
2-5 Kg
0.2 - 0.3 Kg
Toxicology
Laboratory
Clinical
30 Kg
0.5 - 1 Kg
Pilot Plant
Clinical
400
Laboratory
1100 - 1200
80-90 Kg
3 - 4 Kg
Pilot Plant
Clinical
Currently Producing
gt 30 Kg
40000 - 70000
3000-5000 Kg
Commercial
10
Fusion Inhibiton
Reverse transcriptase
T
11
Video on Mechanism of Action of FUZEON
12
Dosing and Administration of FUZEON
13
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.

14
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

15
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

16
Convenience Box 358 x 177 x 202.8mm
17
Convenience Box
"top view"
18
Convenience Box
"overview"
19
Efficacy of FUZEON - The Clinical Trials
20
T-20 clinical synopsis
Phase I/II
TRI-001
Proof of concept
n 17
n 73
TRI-003
Outpatient dosage form
T20-204
Paediatric study
n 14
Phase II
n 70
T20-205
Chronic safety
T20-206
Dose comparison
n 71
n 46
T20-208
Formulation improvements
Pivotal
T20-301
n 491
Phase III
n506
T20-302
Pivotal
T20-305
Safety study
Up to 450
T20-310
Paediatric study
n 48
21
TORO Studies
22
(No Transcript)
23
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
Available options
Individualized background SELECTED FOR MAXIMUM
ACTIVITY
Drug A
Drug B
Drug E
Drug A
Drug C
Drug C
Drug D
24
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

Resistance test information
Individualized background SELECTED FOR MAXIMUM
ACTIVITY
Treatment history
25
TORO-2 Study
26
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 N525 each, randomized 12)
• Optimized Background OB, 3-5 antiretrovirals
  (ARVs) based on history, viral GT/PT (n175)
• Fuzeon (ENF, T-20 90 mg sc bid) OB, (n350)

27
TORO 2Demographics and Baseline Characteristics
ENFOB OB Total (N335) (N169)
(N504) 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
Gender, race and age were balanced across
treatments
28
TORO 2 Summary of AEs Related to any drug in
Original Regimen prior to switch(gt 5 through Wk
24, excluding ISRs)
Adverse Event FUZEON OB OB (N335) (N169) Tot
al 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)
29
TORO 2 Primary Study Endpoint HIV-1 RNA Log
Change from BL at Week 24
OB alone
FUZEON OB
0
N169
N335
-0.65
Change from BL(log10 copies/ml)
-1
-1.43
(Delta0.78, Plt0.0001)
-2
Least Squared Means Log Change from Baseline -
Intent-to-Treat Population (LOCF)
30
TORO 2 Secondary Analysis Response at Week 24
(ITT, DCFailure)
100
FUZEON OB
OB
80
Plt0.0001
60
of Patients
Plt0.0001
43
40
P0.0099
28
21
14
12
20
5.3
0
? 1 log decrease
lt 400 copies/mL
lt 50 copies/mL
from BL
2 visits required to confirm viral load response
31
TORO 2Secondary Analysis Mean CD4 Cell Count
Change from BL at Week 24
100
P0.023
65
Change from BL (Cells/mm3)
50
38
0
OB alone
FUZEON OB
Least Squared Means Change from Baseline
Intent-to-Treat Population (LOCF)
32
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, lt400, lt50 c/mL)
  statistically significant favouring the Fuzeon
  arm
• CD4 cell count change from baseline
  statistically significant favouring the Fuzeon
  arm

33
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 plt0.0001
• TORO 2 -1.43 vs. -0.65 Delta 0.78 plt0.0001
• Sensitivity analyses and analysis of secondary
  virologic and immunologic endpoints consistently
  demonstrated benefit of ENFOB over OB
• Safety
• ISRs occur in almost all patients treatment
  limiting in 3
• Other AEs comparable across treatments

34
TORO 1 / 2Conclusions

• 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

35
TORO 2 (Sub-group Analyses)
36
TORO 2 Demographic subpopulations Subgroup
analysis of mean change from baseline in log10
HIV-1 RNA at week 24 (ITT population)
Gender
Race
Age
lt 40

40
Male
Female
White
Non-White
years
years
0
N8
N109
N148
N161
Change from baseline(log10 copies/mL)

N60
-1

N21


N146
N316
N292
N43
N189
N19
ENF OB
OB
-2
p lt 0.05
Least Squared Means Log Change from Baseline
(LOCF) - Intent-to-Treat Population
37
TORO 2 Baseline viral load and CD4Subgroup
analysis of mean change from baseline in log10
HIV-1 RNA at week 24 (ITT population)
lt 40,000

40,000
lt 100 CD4

100 CD4
3
3
copies/mL
copies/mL
cells/mm
cells/mm
0
N81
N130
N39

Change from baseline(log10 copies/mL)
N85
-1

N169


N258
N77
N166
-2
p lt 0.05
ENF OB
OB
Least Squared Means Log Change from Baseline
(LOCF) - Intent-to-Treat Population
38
TORO 2 Baseline GSS scoreSubgroup 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
0
N31

N50
N60
N5

N4
-1
N33
N45
Change from baseline(log10 copies/mL)
N95


N4
N49
N104
-2
N13
p lt 0.05
-3
ENF OB
OB
Least Squared Means Log Change from Baseline
(LOCF) - Intent-to-Treat Population
39
TORO 2 Baseline PSS scoreSubgroup 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
0
N59

N37
N4
Change from baseline(log10 copies/mL)

-1
N101
N39
N7

N82
N22
N5
N69
N43
N21
-2
p lt 0.05
ENF OB
OB
Least Squared Means Log Change from Baseline
(LOCF) - Intent-to-Treat Population
40
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 lt0.0001 Baseline VL
(per log10 copies/mL) -0.30 -0.47,
-0.12 0.0009 Baseline CD4 count -0.21 -0.28,
-0.14 lt0.0001 (per 100 cells/mm3) PSS -0.19 -0.
26, -0.11 lt0.0001 Total adherence score (per
10) -0.11 -0.19, -0.04 0.0038 Prior LPV/r
experience 0.86 0.65, 1.07 lt0.0001
Replacing PSS with GSS gives similar results
Adherence based on 4 day recall
41
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

42
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)

43
Activities of Daily Living SurveyTORO 1 and 2
44
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
• n661 (Toro 1 2)
• Evaluated patients experience with preparing and
  injecting
• Administered at 8 and 24 weeks (prior to seeing
  clinician)

45
Toro 1 2 - Activities of Daily Living
(SIS Survey)
68.1
Giving yourself injections
81.4
Keeping medication refrigerated
74.4
Dissolving medication in water
92.4
Disposing of needles and vials
0
20
40
60
80
100
Patient Responses ()
Very easy or Easy
Neutral
Difficult
Very difficult
Green et al., Poster, HIV6, Glasgow
46
Toro 1 2 - Activities of Daily Living
77.8
Participating in recreational activities/sports
70.1
Maintaining privacy about your health
84.2
Socializing (or interacting) with family or
friends
77.5
Being intimate or having sexual relations with a
partner
68.6
Traveling away from home
89.2
Getting around locally
84.7
Working at a job or attending school
90.4
Sleeping
0
20
40
60
80
100
Patient Responses ()
Not at all or a little
Moderately
Quite a bit
Extremely
47
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.

48
Injection Site Reactions (ISR)
49
Picture of Injecting Site Reactions (ISR)
50
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.

51
ISRs - Drug-demographic interactions

• Demographic Subpopulations
• Gender (male or female)
• Race (white or non-white)
• Age (lt40yrs 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

52
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)

53
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

54
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.

55
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?)

56
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)

57
FUZEON and RESISTANCE
58
Resistance testing

• Drug resistant HIV can be identified by two in
  vitro methods
• Genotyping and
• Phenotyping

59
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.

60
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.

61
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 (n18)
• G36D (n15)
• G36S (n11)
• N43D (n10)
• N42T (n5)
• At the time of protocol defined virological
  failure, viruses from a total of 31/40 (78)
  patients showed substitutions in gp41 aa 36-45.

62
Resistance testing - Phenotype
63
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 (n130)
• Using a JC53-BL cell assay mean EC50 was 0.16
  ?g/ml (n35) (Derdeyn et al)
• Using a PhenoSense Assay the mean EC50 was 0.26
  ?g/ml (n612)
• All are valid assays

64
Enfuvirtide susceptibility of isolates from
Phase II clinical studies
GM2SD0.218 µg/mL
Geometric Mean (GM) EC50 0.020 µg/mL
The relationship between in vitro susceptibility
and in vivo activity has not been established
65
T20-301T20-302Histogram of Baseline EC50 (µg/mL)
GM2SD1.956 µg/mL
Geometric Mean (GM) EC50 0.259 µg/mL
66
Patients carrying the least sensitive virus
pre-treatment respond similarly to
FUZEONtreatment

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

67
Fold-change in ENF susceptibility at virological
failure through week 24
68
PHENOTYPIC CHANGES IN VIRUSES EMERGING
WITH SINGLE T-20 RESISTANCE MUTATIONS PHASE 2
STUDIES
Poster 22 Seville, 2002
69
PHENOTYPIC CHANGES IN VIRUSES EMERGING
WITH DOUBLE T-20 RESISTANCE MUTATIONS PHASE 2
STUDIES
Poster 22 Seville 2002
70
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

71
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

72
Failure rates for FUZEONOB 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)
73
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

74
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

75
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

76
Paediatrics
77
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

78
Current and future paediatric clinical program
As of March 2003 Conducted by Pediatric AIDS
Clinical Trials Group (PACTG)
79
Current and future paediatric clinical program
As of March 2003 Conducted by Pediatric AIDS
Clinical Trials Group (PACTG)
80
Paediatric data currently available
(Nov 02 safety update)

• Patient
• 47 paediatric pts included
• 35 patients aged 616 yrs
• Exposure
• 35 paediatric patients 616 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 316 years
• 20 patients 616 years

81
Dose recommendation for patients 6 16 yrs
safety (2mg/kg BID dose)

• 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

82
Dose recommendation for patients 6 16 yrs
(2mg/kg BID dose)
Cross-study comparison
Double- or triple-class experienced
Double-class experienced
ND
?1 log decrease from BL
lt400 copies/ml
lt50 copies/ml
83
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

84
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

85
Access in the UK
86
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)

87
EAP (IPS) Global criteria

• Male and female HIV-1 infected adults or
  adolescents (³ 16 years of age)
• CD4 lymphocyte count ? 100 cells/mm3 and HIV-1
  RNA viral load gt 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

88
FUZEONIPS- Status (22nd April 03) - Location of
patients

• London (20)
• Royal London (1)
• UCL (3)
• St Marys (3)
• Chelsea Westminster (7)
• London and Barts (3)
• St Thomas (1)
• Kings (1)
• Outside London (17)

89
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

90
When to use enfuvirtide ?
91
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

92
Development plans and T-1249
93
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

HR1
HR2
FP
cc
NH2
COOH
tm
ENF
T-1249
94
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.
95
T1249-102

• 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

96
T1249-102 Study Design
Stable antiretroviral background
ENF with VL ? 5,000
T-1249 192 mg x 10 days
Stop ENF
Day 5
Day 11
Day 8
BL (Day 1) Start T-1249
Viral Load taken at BL and each Study visit GT
and PT performed at BL (Day 1) and at Day 11
97
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 (n25) 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

98
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

99
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
  (n15)

100
T1249-102Treatment-Emergent Serious Adverse
Events (SAE)
Five SAEs reported in three patients
3 (12 SAP)
Patient Preferred Term N () Related
T-1249 200764 Alanine aminotransferase (ALT)
1 (4) No increased Aspartate
aminotransferase (AST) 1 (4) No increased 2027
30 Bronchitis acute NOS 1 (4) No 200148 Pneumoni
a 1 (4) No Respiratory failure 1 (4) No
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) n25
101
T1249-102Incidence TE Grade 3 4 Laboratory
Toxicities (reported by n3 patients 12)
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)
All reported from the same patient prior to
demise with multiorgan failure
102
T1249-102 Log10 HIV RNA Mean and Median Change
from Baseline (ITT)
Day 11 Median -1.12 (CI -1.50 -0.83)
N24 22 24
24
103
Percent of patients with ? 1 log10 drop in HIV
RNA according to length of ENF therapy after VF
Median drop -1.6
Percent of patients with ? 1 log drop
Median drop -0.94
7/7
8/17
24-48 wk gt 48 wk
104
T1249-102 Percent of patients with ? 1.0 log
Decline (ITT)
MissingFailure
105
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

106
T1249Timelines

• Phase II trials will start in late 2003
• Followed by Phase 111 trials
• Hope to launch in 2006

107
BACK -UPS
108
Mechanism of Action
109
Representation of the HIV binding process
110
Working model of HIV fusion
111
Representation of gp41 showing the HR1 and HR2
region
112
Working model of HIV fusion inhibition
113
How do we interpret resistance tests?One
possible approach
PSS Phenotypic sensitivity score
GSS Genotypic sensitivity score
The number of drugs in a regimen to which a
patients 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
patients virus is considered sensitive by
genotyping Genotypic resistance determined by
mutation analysis algorithms

• 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 gt2 is preferable if possible

114
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

115
A test may give only a partial answer to drug
sensitivity
Low fitness of resistant strains
Patient stops drugs
Reversion to wild type

• BUT
• Undetectable minority populations remain
• HIV sanctuary sites in body compartments
• Latently infected CD4 cells

Cause resistance to ARCHIVE RECHALLENGE ?
RE-EMERGENCE

• 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

116
TORO- 1 Study
117
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.
118
TORO 1 Demographics and Baseline Characteristics
ENFOB OB Total (N326) (N165)
(N491) 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
119
TORO 1Patient Disposition (ITT)
Discontinuations ENF OB 11.3, OB 21.4 For
further details see poster LbOr19b
120
TORO 1 Summary of AEs Related to any drug on
Original treatment prior to switch(gt 5 on ENF
OB, through Wk 24, Excluding ISRs)
Adverse Event ENF OB OB (N326) (N165) 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)
121
TORO 1 Primary Study Endpoint HIV-1 RNA Log
Change from Baseline at Week 24
OB alone
Fuzeon OB
0
N165
N326
Change from BL(log10 copies/ml)
-0.76
-1
-1.70
-2
(Delta0.93, Plt0.0001)
Least Squared Means Log Change from Baseline -
Intent-to-Treat Population (LOCF)
122
TORO 1 Secondary Analysis Response at Week 24
(ITT, DCFailure)
100
Fuzeon OB
OB
80
Plt0.0001
Plt0.0001
52
60
of Patients
37
P0.0002
40
29
20
16
20
7.3
0
lt 50 copies/mL
?1 log decrease from BL
lt 400 copies/mL
2 visits required to confirm viral load response
123
TORO 1 Time to Virological Failure
1
0.75
Plt0.0001
ENFOB
1-Prob (Virological Failure)
0.5
OB
0.25
Time to protocol definedVF starts at week 6
0
0
4
8
12
16
20
24
Study Week
For definition of virologic failure, see
Back-up slide
124
TORO 1 CD4 Cell Count Change from Baseline at
Week 24
100
76
P0.0001
Change from BL (Cells/mm3)
50
32
0
OB alone
Fuzeon OB
Least Squared Means Change from Baseline
Intent-to-Treat Population (LOCF)
125
TORO 1 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 favoring the Fuzeon arm
• Secondary endpoints
• Responder analyses (?1 log drop, lt400, lt50 c/mL)
  statistically significant favoring the Fuzeon arm
• CD4 cell count change from baseline
  statistically significant favoring the Fuzeon
  arm

126
TORO 2Patient Disposition (ITT)
Discontinuations ENF OB 17.0, OB 14.7 For
further details see poster LbOr19a
127
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) lt25 mm
gt25 mm gt50 mm gt85 of skin redness (size of a
but lt50 mm but lt85 mm at the site quarter)
of injection Induration diameter (mm)
Slight present but lt25 gt25 mm gt50 mm of
palpable but lt50 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 responding to
analgesics   Grade 4 local reactions require a
clinic visit within 12 to 24 hours of the event