Antiretroviral Activity and Tolerability of Reverset Dd4FC, a New FluoroCytidine Nucleoside Analog w

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Antiretroviral Activity and Tolerability of
Reverset (D-d4FC), a New Fluoro-Cytidine
Nucleoside Analog when used in Combination
Therapy in Treatment-Experienced Patients
Results of Phase IIb Study RVT-203

• C. Cohen, C. Katlama, R. Murphy, J. Gathe, C.
  Brinson, G. Richmond, P.-M. Girard, J. Fessel, A.
  Liappis, E. Puglia, B. Rodwick, J. Nadler, W.
  OBrien, K. Arasteh, M. Otto, S.
  Erickson-Viitanen, R. Levy
• 3rd IAS Conference
• July 24-27, 2005
• Rio de Janeiro, Brazil

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Background

• Preclinical studies demonstrated
• Active with viral mutants resistant to 3TC, AZT,
  TDF, other NRTIs, NNRTIs and PIs
• Long intracellular half life (17 hours)
• No mitochondrial toxicity or lactic acid increase
  (in vitro)
• 10-day add-on dosing demonstrated
• VL decrease of 0.8 logs with 200 mg qd dosing in
  therapy-experienced patients
• VL decrease of 1.8 logs with 200 mg qd in
  therapy-naïve patients

Reverset
NH2
(D-D4FC)
N
F
O
N
O
HO
b-D-2,3-didehydro-2,3- dideoxy-5-fluorocytidin
e
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RVT-203 Study Design

• Treatment experienced patients viremic (gt2000
  c/mL) on current regimen N199
• Randomized, placebo-controlled, double-blind,
  parallel dose group 50, 100, 200 mg once daily
• USA, France, Germany, 25 centers total
• Stratification by TAMs 0-3 and 4-6 based on
  screening genotype
• 3 phases

2-Wk Add-on
14-Wk treatment with Optimized Background Regimen
8 Wk Placebo ? Cross-over
0 2
16
24 Weeks on study
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Endpoints

• Primary
• Mean Change in viral load (VL) to week 2 and 16
• Safety
• Secondary
• Proportion with gt1 log decline in VL
• Virologic response in patients who did / did not
  optimize at Week 2

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Baseline Characteristics
Overall mean baseline viral load 4.5 log
Overall mean baseline CD4 count 248 cells/mm3

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Change in Viral Load from Baseline 2-Week Add-On
Phase
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Effect of NRTIs in Baseline Regimenon 2-week
Viral Load Decline with RVT 200 mg
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Effect of RT Mutations on 2-Week Viral Load
Decline With 200 mg RVT

• Note data for K65R and M184V alone are pooled for
  all doses

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Study RVT-203 16 week Efficacy Results
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Sub-Group Analyses at Week 16
p lt 0.05
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Effect of Concurrent 3TC/FTC on Week 16 Response
Rates

• Use of 3TC/FTC not randomized
• Post-hoc analysis

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Presence of M184V Does Not Impact 16-Week
Response to 200 mg RVT
Presence/absence of M184V with TAMs
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Moderate to Severe Clinical Adverse Events to 16
WeeksEvents Considered at Least Possibly Related
No other events were reported in more than one
patient
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Hyperlipasemia Grade 4
RVT should not be used with ddI
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Pancreatitis

• Cases of pancreatitis, all on 100 mg RVT
• N3 symptomatic pancreatitis
• One patient taking full dose (400 mg) ddI
  tenofovir
• One patient taking 250 mg ddI plus 1.5X dose of
  tenofovir (450 mg)
• One patient with ongoing alcohol abuse
• N1 abnormal ultrasound but normal CT scan in an
  asymptomatic patient with grade 4 lipase
• Taking recommended doses of ddI tenofovir
• All patients recovered
• Rapid, symptomatic and radiographic recovery
• No complications
• Lipase/amylase levels recovered more slowly

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Other Possibly Related Serious Adverse Events in
Patients on RVT

• Anemia (1 patient on 200 mg RVT)
• Also receiving AZT
• Neutropenia (1 patient on 200 mg RVT)
• Worsening neutropenia when started on TMP-SMX for
  PCP
• Hypertriglyceridemia (1 patient on 100 mg RVT)
• Developed worsening hypertriglyceridemia when
  started on fosamprenavir 1400 mg and ritonavir
  200 mg once daily
• Pancytopenia (1 patient on 200 mg RVT)
• Developed anemia (Grade 3), neutropenia (grade 3)
  and thrombocytopenia (Grade 2), resolved with
  discontinuation of study medication

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Conclusions

• 200 mg Reverset provides antiviral suppression
  in highly ARV-experienced patients
• 2-week add-on -0.7 logs
• -1.1 logs without 3TC/FTC
• 16 weeks 54 response overall (gt -1.0 logs)
  
• 80 response without 3TC/FTC vs.
• 46 placebo with 3TC/FTC
• -1.4 logs without 3TC/FTC
• Reverset is generally well tolerated
• Asymptomatic hyperlipasemia when used with ddI
• RVT should not be used with ddI
• Reverset activity retained with key mutations
• To date, no novel mutations identified in
  RVT-exposed patients
• No K65R emerged in RVT-exposed patients
• Reverset warrants further development
• Phase III trial planning in progress

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Acknowledgments

• Participating Subjects
• Investigators
• United States France
• Calvin Cohen Rob Murphy Christine Katlama
• Joseph Gathe Cynthia Brinson Pierre-Marie
  Girard
• Jeffrey Fessel Gary Richmond
• Angelike Liappis Edgardo Puglia Germany
• Barry Rodwick Jeffrey Nadler Keikawus Arasteh
• William OBrien Steven OMarro Dirk Schurmann
• Jeffrey Galpin George Beatty Schlomo Staszewski
• Donna Mildvan Kathleen Squires Hans-Juergen
  Stellbrink
• Corklin Steinhart Gerald Pierone Albrecht Stoehr
• Sponsors
• Incyte Corporation Pharmasset, Inc.