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Enfuvirtide (T-20)

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

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Enfuvirtide (T-20)

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  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 kg180 mg Capacity being created

  9. Facility Under Construction 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 Laboratory Toxicology 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 > 30 Kg 40000 - 70000 3000-5000 Kg Commercial

  10. Fusion Inhibitors Nucleus RNA Protease DNA Reverse transcriptase inhibitors Protease inhibitors 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 n = 17 Phase I/II TRI-001 Proof of concept n = 73 TRI-003 Outpatient dosage form n = 14 T20-204 Paediatric study Phase II n = 70 T20-205 Chronic safety n = 71 T20-206 Dose comparison n = 46 T20-208 Formulation improvements n =491 T20-301 Pivotal Phase III n=506 T20-302 Pivotal Up to = 450 T20-305 Safety study n = 48 T20-310 Paediatric study

  21. TORO Studies

  22. 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. Available options Individualized background SELECTED FOR MAXIMUM ACTIVITY New agent Drug A Drug B Drug E Drug A Drug C Drug C Drug D

  23. 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

  24. TORO-2 Study

  25. 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)

  26. TORO 2:Demographics and Baseline Characteristics 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 Gender, race and age were balanced across treatments

  27. 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%)

  28. TORO 2: Primary Study Endpoint HIV-1 RNA Log Change from BL at Week 24 FUZEON + OB OB alone 0 N=335 N=169 -0.65 Change from BL(log10 copies/ml) -1 -1.43 (Delta=0.78, P<0.0001) -2 Least Squared Means Log Change from Baseline - Intent-to-Treat Population (LOCF)

  29. TORO 2: Secondary Analysis Response at Week 24 (ITT, DC=Failure) 100 FUZEON + OB OB 80 P<0.0001 60 % of Patients P<0.0001 43 40 P=0.0099 28 21 14 12 20 5.3 0  1 log decrease < 400 copies/mL < 50 copies/mL from BL 2 visits required to confirm viral load response

  30. TORO 2:Secondary Analysis Mean CD4+ Cell Count Change from BL at Week 24 100 P=0.023 65 Change from BL (Cells/mm3) 50 38 0 FUZEON + OB OB alone Least Squared Means Change from Baseline Intent-to-Treat Population (LOCF)

  31. 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

  32. 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% • Other AEs comparable across treatments

  33. 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

  34. TORO 2 (Sub-group Analyses)

  35. TORO 2: Demographic subpopulations: Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population) Gender Race Age < 40 = 40 Male Female White Non-White years years 0 N=8 N=109 N=148 N=161 Change from baseline(log10 copies/mL) * N=60 -1 * N=21 * * N=146 N=316 N=292 N=43 N=189 N=19 ENF + OB OB -2 *p < 0.05 Least Squared Means Log Change from Baseline (LOCF) - Intent-to-Treat Population

  36. TORO 2: Baseline viral load and CD4:Subgroup analysis of mean change from baseline in log10 HIV-1 RNA at week 24 (ITT population) < 40,000 = 40,000 < 100 CD4 100 CD4 = 3 3 copies/mL copies/mL cells/mm cells/mm 0 N=81 N=130 N=39 * Change from baseline(log10 copies/mL) N=85 -1 * N=169 * * N=258 N=77 N=166 -2 *p < 0.05 ENF + OB OB Least Squared Means Log Change from Baseline (LOCF) - Intent-to-Treat Population

  37. 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 0 N=31 * N=50 N=60 N=5 * N=4 -1 N=33 N=45 Change from baseline(log10 copies/mL) N=95 * * N=4 N=49 N=104 -2 N=13 *p < 0.05 -3 ENF + OB OB Least Squared Means Log Change from Baseline (LOCF) - Intent-to-Treat Population

  38. 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 0 N=59 * N=37 N=4 Change from baseline(log10 copies/mL) * -1 N=101 N=39 N=7 * N=82 N=22 N=5 N=69 N=43 N=21 -2 *p < 0.05 ENF + OB OB Least Squared Means Log Change from Baseline (LOCF) - Intent-to-Treat Population

  39. 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

  40. 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

  41. 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)

  42. Activities of Daily Living SurveyTORO 1 and 2

  43. 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)

  44. 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

  45. 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

  46. 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.

  47. Injection Site Reactions (ISR)

  48. Picture of Injecting Site Reactions (ISR)

  49. 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.

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