NV1FGF Gene Therapy on Amputation-
Free Survival in Critical Limb Ischemia -
  Phase 3 Randomized Double-Blind
 Placebo-Co...
Presenter Disclosure Information
• William R. Hiatt, MD:
  University of Colorado & CPC Clinical Research

• TITLE:
  NV1F...
PAD Clinical Classification

                Fontaine                                     Rutherford
     Stage           ...
Anatomy of CLI

SFA        Tibial      Clinical




                                  4
CLI Epidemiology
                      US/EU incidence 70,000-90,000/year

              Primary Treatment                ...
Background and Rationale
• Therapeutic angiogenesis         • Human acidic growth
 via gene tranfer of angiogeneic     fac...
NV1FGF Phase 2 (TALISMAN study)


    • 125 patients with CLI and ischemic ulcers
      (Fontaine IV) unsuitable for revas...
NV1FGF Phase 2 Results
                                        Placebo            NV1FGF
                                 ...
TAMARIS Study
 525 CLI patients with skin lesions                Randomized to NV1FGF 4 mg
 (Fontaine IV), unsuitable for ...
TAMARIS trial design
               (replicates phase 2 including dosing)
                                                ...
Endpoints
Primary endpoint:
  • First occurrence of major amputation (above the ankle)
    of the treated leg or death fro...
Inclusion Criteria
• Patient > 50 years, with critical limb ischemia with ischemic
  lesions (ulcers or gangrene)

• Unsui...
Exclusion Criteria
• Major amputation of treated leg (prior or planned)

• Infected gangrene

• Non-ischemic ulcer (venous...
Baseline Demographics
                                Placebo       NV1FGF

Number                            259         ...
Primary Endpoint
                                        Time to Major Amputation or Death
                               ...
TAMARIS Secondary Endpoints
         Time to Major Amputation and Time to Death
                                  30      ...
Safety

                                  Placebo       NV1FGF
Overall safety                     N=259         N=266



A...
NV1FGF Phase 3 Trial
                   TAMARIS Conclusions
• Largest gene therapy trial in CLI patients with ischemic ski...
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AHA: TAMARIS

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AHA: TAMARIS

  1. 1. NV1FGF Gene Therapy on Amputation- Free Survival in Critical Limb Ischemia - Phase 3 Randomized Double-Blind Placebo-Controlled Trial (TAMARIS) William R. Hiatt, Iris Baumgartner, Sigrid Nikol, Eric Van Belle, Vickie Driver, Lars Norgren, Jill Belch (TAMARIS steering committee) 1
  2. 2. Presenter Disclosure Information • William R. Hiatt, MD: University of Colorado & CPC Clinical Research • TITLE: NV1FGF Gene Therapy on Amputation-Free Survival in Critical Limb Ischemia - Phase 3 Randomized Double-Blind Placebo-Controlled Trial (TAMARIS) • FINANCIAL DISCLOSURE: Grants/Research Support from Sanofi-Aventis • UNLABELED/UNAPPROVED USES DISCLOSURE: Use of NV1FGF (riferminogene pecaplasmid) is investigational only 2
  3. 3. PAD Clinical Classification Fontaine Rutherford Stage Clinical State Grade Category Clinical State I Asymptomatic 0 0 Asymptomatic II a Mild IC I 1 Mild IC II b Moderate-severe IC I 2 Moderate IC I 3 Severe IC III Ischemic rest pain II 4 Ischemic rest pain III 5 Minor tissue loss IV Ulcers, gangrene III 6 Major tissue loss 3 TASC Working Group. J Vasc Surg. 2000;31(1 suppl):S1-S296.
  4. 4. Anatomy of CLI SFA Tibial Clinical 4
  5. 5. CLI Epidemiology US/EU incidence 70,000-90,000/year Primary Treatment A year later Primary Continuing CLI amputation 20% CLI resolved 25% 25% Revascularization 50% Medical treatment Alive amputated only Dead 30% 25% 25% 5 TASC II Eur J Vasc Endovasc Surg 2007;33:1-75
  6. 6. Background and Rationale • Therapeutic angiogenesis • Human acidic growth via gene tranfer of angiogeneic factor (FGF1) protein growth factors may improve promotes activation, migration, perfusion the development of proliferation and differentiation of new blood vessels relevant vascular cells • NV1FGF is a non-viral recombinant DNA plasmid, containing a gene encoding FGF1 6
  7. 7. NV1FGF Phase 2 (TALISMAN study) • 125 patients with CLI and ischemic ulcers (Fontaine IV) unsuitable for revascularization • Randomized to 16 mg of NV1FGF or placebo (4 mg administered as 8 IM injections every two weeks for a total of 4 doses) • Primary endpoint = Complete ulcer healing at 25 weeks • Secondary endpoints = major amputations, death, amputation free survival at 12 months 7 Nikol, et Al. Mol Ther 2008;16:972-8
  8. 8. NV1FGF Phase 2 Results Placebo NV1FGF Hazard ratio P value (N=56) (N=51) Primary end point at week 25 Complete healing of at least one 8 (14.3) 10 (19.6) - 0.514* ulcer selected at baseline Secondary end points over 52 weeks Amputation rate All 31 (55.4) 19 (37.3) 0.498 0.015b Major 19 (33.9) 8 (15.7) 0.371 0.015b Death rate 13 (23 2) 6 (11.8) 0.460 0.105b Combined major amputation and 29 (51.8) 14 (27.4) 0.435 0.009b death rates 1 Death or Major Amputation 0,8 NV1FGF 0,6 0,4 Placebo 0,2 Hazard ratio = 0.43 (Log Rank p=0.009) Days 0 0 75 15 225 300 375 Placebo N=56 47 37 29 26 Nv1fgf N=51 47 43 37 35 8 Nikol. et Al. Mol Ther 2008;16:972-8
  9. 9. TAMARIS Study 525 CLI patients with skin lesions Randomized to NV1FGF 4 mg (Fontaine IV), unsuitable for standard every two weeks x 4 or placebo revascularization Double blind assessment, 30 countries (US, Canada, South stratification by country and America, Europe, Asia, South Africa) diabetes 30 countries, 171 sites 9 Largest international phase 3 trial in CLI patients unsuitable for revascularization
  10. 10. TAMARIS trial design (replicates phase 2 including dosing) 12 Mo efficacy & safety analysis N=245 NV1FGF 4mg R N=245 PLACEBO Screening R 2 Wk 4 Wk 6 Wk 3 Mo 6 Mo 9 Mo 12 Mo up to 36 Mo D-43 to D-15 D1 D15 +/-2 D29 +/-2 D43 +/-2 D90 +/-7 D180 +/-7 D270 +/-7 D360 +7 Follow-up Screening Period Treatment Phase Follow-up period Exploratory Safety Follow-Up period 10
  11. 11. Endpoints Primary endpoint: • First occurrence of major amputation (above the ankle) of the treated leg or death from any cause over 12 months Secondary endpoints: • All amputations • Death • Ulcer healing • Pain relief • Functional status 11
  12. 12. Inclusion Criteria • Patient > 50 years, with critical limb ischemia with ischemic lesions (ulcers or gangrene) • Unsuitability for revascularization assessed by vascular surgeon • (verified by independent adjudication committee) • CLI confirmed by hemodymanic criterion: • Ankle pressure <70mmHg, or Toe pressure <50mmHg or Transcutaneous pressure of oxygen (TcPo2) < 30mmHg • Inflow to femoral artery confirmed by imaging • Negative cancer screen 12
  13. 13. Exclusion Criteria • Major amputation of treated leg (prior or planned) • Infected gangrene • Non-ischemic ulcer (venous or neuropathic only) • Acute cardiovascular event prior 3 months • Proliferative retinopathy or active/recent malignancy 13
  14. 14. Baseline Demographics Placebo NV1FGF Number 259 266 Mean Age (Range) 69 (50-92) 71 (50-95) Male 181 (69.9%) 184 (69.2%) Current/Former smoker 165 (63.7%) 156 (58.7%) Hypertension 213 (82.2%) 233 (87.6%) Hyperlipidemia 153 (59.1%) 164 (61.7%) Diabetes 141 (54.4%) 139 (52.3%) Angina/unstable angina 91 (35.1%) 72 (27.1%) Myocardial infarction 69 (26.6%) 61 (22.9%) Atrial fibrillation 53 (20.5%) 46 (17.3%) Stroke 38 (14.7%) 40 (15.0%) Congestive heart failure 39 (15.1%) 53 (19.9%) 14
  15. 15. Primary Endpoint Time to Major Amputation or Death 40 NV1FGF 35 Primary outcome event rate (%) 30 Placebo 25 20 15 10 Placebo NV1FGF Hazard ratio P N=259 N=266 (95% CI) 5 Major amputation 86 96 1.11 0.48 or death (33.20%) (37.07%) (0.83, 1.49) 0 0 3 6 9 12 Number at Risk Months since randomization Placebo 259 217 196 184 173 NV1FGF 266 211 193 179 169 15
  16. 16. TAMARIS Secondary Endpoints Time to Major Amputation and Time to Death 30 30 NV1FGF Major amputation rate (%) 25 NV1FGF 15 Death rate (%) 20 Placebo Placebo 15 10 10 5 5 0 0 0 3 6 9 12 0 3 6 9 12 Number at Risk Months since randomization Number at Risk Months since randomization Placebo 259 217 196 184 173 Placebo 259 242 234 228 220 NV1FGF 266 211 193 179 169 XRP0038 266 247 240 231 219 Placebo NV1FGF Hazard ratio P N=259 N=266 (95% CI) Major amputation 55 (21.24%) 67 (25.87%) 1.20 (0.84, 1.72) 0.31 Death 39 (15.06%) 46 (17.76%) 1.15 (0.75, 1.76) 0.53 16
  17. 17. Safety Placebo NV1FGF Overall safety N=259 N=266 Adverse events 205 (79.8%) 214 (80.5% ) Serious adverse events 151 (58.8%) 163 (61.3%) Adverse event leading to death 36 (14.0%) 35 (13.2%) Placebo NV1FGF Relative risk Events of special interest N=259 N=266 (95% CI) P Ischemic heart disease 26 (10.1%) 27 (10.2%) 1.00 (0.60, 1.67) 1.00 Malignant neoplasm 4 (1.6%) 7 (2.6%) 1.69 (0.50, 5.71) 0.55 Retinal disorders 15 (5.8%) 11 (4.1%) 0.71 (0.33, 1.51) 0.42 Renal impairment 15 (5.8%) 20 (7.5%) 1.29 (0.67, 2.46) 0.49 17
  18. 18. NV1FGF Phase 3 Trial TAMARIS Conclusions • Largest gene therapy trial in CLI patients with ischemic skin lesions, unsuitable for revascularization • NV1FGF 4 doses of 4 mg did not improve amputation-free survival • No definitive safety signal over 1 year and 3 year long term safety follow up in progress • Design and oversight by Independent Steering Committee, Data Safety Monitoring Board and Adjudication Committee • Results were consistent among regions, by diabetes status and other relevant subgroup analysis • Difference between phase 2 TALISMAN and phase 3 TAMARIS outcomes may be explained by a chance positive finding (type 1 error) • Confirms the importance of large well-conducted RCTs 18

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