West Nile Virus Treatment

1
West Nile VirusTreatment

• Randomized Clinical
• Trial (RCT) Studies
• Reviewed by Carol Glaser
• 6th WNV national meeting, Feb 2005
• San Jose, CA

2
West Nile neuroinvasive cases vs. Enrollment in
RCT

• Total number of West Nile Neuroinvasive Cases in
  2004
• In US 900
• In California 289
• Total number enrolled in RCT
• In US 30
• In California lt10
• Break-out session to follow with representatives
  from the clinical trials, infectious disease
  physicians, neurologists, and IRB

3
West Nile Virus Outcome Mortality

• Case fatality of WNV-hospitalized cases
  worldwide 5-18
• US case fatality WN encephalitis 9
• Nash D, NEJM 2001
• Tsai T, Lancet, 1998
• Chowers MY, EID, 2001
• Petersen LR, JAMA, 2003

4
West Nile Virus Outcome Morbidity

• Not well studied
• Of 19 hospitalized patients in NY/NJ only 37
  were fully recovered at discharge
• Of 64 hospitalized patients in Ontario, most
  had persistent neurologic deficits 30 days after
  discharge
• Of those with acute flaccid paralysis -- limited
  recovery
• Emerg Inf Dis 2001
• Canadian Med Assn J 2003
• Emerg Inf Dis 2003

5
West Nile VirusAvailable Treatment Options

• Treatment
• primarily supportive care
• many patients do well with no specific treatment
• 3 Randomized placebo-controlled trials
• Interferon
• Israeli IVIG
• 3rd generation anti-sense

6
WNV Randomized Clinical Trials Proposed
Mechanisms

• Interferon immune stimulator
• Israeli IVIG passive immunity
• 3rd generation anti-sense inhibit viral
  replication

7
WNV Randomized Clinical Trials Prior experience

• All 3 products, successful treatment
• Animal models
• Human case reports
• Drug trials not blinded
• See appendix for references

8
WNV Randomized Clinical Trials Enrollment

• Total number Total number
• needed enrolled
• Interferon 60 3
• Israeli IVIG 100 27
• 3rd generation anti-sense 50 0

9
WNV Randomized Clinical Trials Enrollment
Criteria

• Fairly similar between studies
• gt18 years of age
• Patients with evidence of encephalitis/myelitis
  OR
• at high risk for development of
  encephalitis/myelitis (immunosuppression, age
  gt40-50 years varies by study)
• Laboratory diagnosis not needed for initial
  enrollment in most cases (but laboratory
  confirmation needed subsequently)

10
WNV Randomized Clinical Trials Study Design

• Interferon
• 11 treatment vs placebo
• IVIG
• 3 arms (311)
• Israeli IVIG
• Standard IVIG
• Placebo
• 3rd generation anti-sense
• 41 treatment vs placebo

11
WNV Randomized Clinical Trials Outcome
Measurements

• Slight variation between studies
• Primary outcome difference between the NIH
  Stroke Scale at randomization and after 3 months
  (Interferon and IVIG)
• All studies looking at multiple intervals
  throughout the first year

12
WNV Randomized Clinical Trials Reimbursement

• All studies provide site reimbursement
• Amount variable by study

13
Break-out Discussion

• Difficulties in enrollment?
• IRB issues
• Lack of awareness
• Transferring between facilities logistical
  payment issues, patient too ill for transport
• Lack of reimbursement for time
• Preference for study drug (and not placebo)
• Too late for enrollment
• Misinformation about necessity of prior serologic
  documentation

14
Appendix

• Basic information on specific trials
• (please see individual websites for more detailed
  information)

15
Available RCT studies in US

• A Randomized Double-Blinded, Placebo Controlled
  Trial of Alpha-Interferon (Alferon) Therapy for
  West Nile Meningoencephalitis (Protocol WN-102)
• A Phase I/II Randomized, Placebo-controlled Trial
  to Assess the Safety and Efficacy of Intravenous
  Immunoglobulin G (Omr-IgG-am) Containing High
  Anti-West Nile Virus Antibody Titers in Patients
  With, or at High Risk for Progression to West
  Nile Virus (WNV) Encephalitis and/or Myelitis.
  Sponsored by National Institute of Allergy and
  Infectious Diseases (NIAID), National Institutes
  of Health
• An Exploratory Study of the Safety, Tolerability,
  Pharmacokinetics and Potential Effectiveness of
  AVI-4020 Injection in Patients Presenting with
  Presumptive Acute Neuroinvasive West Nile Virus
  (WNV) Disease

16
WNV Treatment Trial 1 Interferon Background

• Interferon alpha-2b
• Used to treat Hepatitis C (related virus)
• In vitro
• Interferon alpha-2b inhibited replication at
  relatively low concentrations
• Animal studies
• Increased mean survival time of SCID-treated mice
  infected with related flavivirus
• Reduced viral RNA in serum, brain and spleen
• Proposed Mechanism
• Stimulates cellular antiviral activity, enhances
  bodys host defenses (anti-viral replication has
  also been proposed as mechanism of action)
• Antimicrobial Agents Chemother 200347777

17
WNV Treatment Trial 1 Interferon Background

• Study of SLE patients found benefit with early
  initiation of interferon decreased severity at 3
  weeks (non-randomized, not blinded, historic
  controls)
• Pilot study 2002 and 2003 of WNV encephalitis
• Randomized, not blinded, multi-center
• N15 Rx with Interferon alpha-2b x 2 weeks
• N8 usual supportive care
• Treated group had a significant improvement vs no
  Rx (based on mean change of the NIHSS at 3 weeks)
• Side effects interferon reversible neutropenia,
  hepatitis
• J Infect Dis 2004, 1901084-7
• 44th ICAAC presentation, Washington, Nov 04

18
West Nile treatment trial 1Interferon trial

• Goal enroll 60 patients (3 enrolled to date)
• Randomized placebo-controlled, blinded study
• Interferon alpha-N3 will be used
• Better tolerated than IFN alpha-2b with less
  neutropenia, lymphopenia and fever

19
WNV Treatment Trial 1 InterferonContact
Information

• James Rahal (JJR9002_at_nyp.org)
• Wehbeh Wehbeh (wew9004_at_nyp.org)
• phone [phone]
• http//www.nyhq.org/posting/rahal.html

20
WNV Treatment Trial 2 IVIG Background

• Omrix (Israeli company) partnering with NIAID
• Immunoglobulin that contains antibodies to WNV
• Developed from plasma of Israeli donors with high
  level of antibodies to WNV
• Goal to enroll 100 hospitalized patients gt 18
  years with WNV-related encephalitis
• 3 groups (311)
• WNV-IVIG (Omr-Ig-am)
• standard IVIG (from U.S.)
• Placebo

21
WNV Treatment Trial 2 IVIG Background

• dramatic response to Omr-IgG-am 70 yr old,
  immunocompromised patient
• rapid improvement 42 yr old lung transplant
• 6 other cases 2 improved, 2 no change, 2 death
• Prophylactic and therapeutic efficacy in treating
  West Nile virus in mice
• Emerg Infect Dis, 2001
• Transplant ID 2002
• J Infect Dis, 2003
• J Infect Dis, 2003

22
WNV Treatment Trial 2 IVIGContact Information

• Laura Riser, CASG Clinical Administrator,
• University of Alabama
• [phone] (lriser_at_peds.uab.edu)
• Penny Jester, CASG Project Manager,
• University of Alabama
• [phone] (pjester_at_peds.uab.edu)
• http//www.clinicaltrials.gov/show/NCT00068055

23
WNV Treatment Trial 3 3rd Generation
Anti-sense Background

• 3rd Generation Antisense compound AVI-4020
• Neutral charge (less toxicity)
• Not degraded by serum and/or cellular degradative
  enzymes
• Excreted unchanged via the urinary tract
• Interferes with WNV mRNA translation-? prevents
  WNV replication
• Animal studies (rats/monkeys)
• AVI-4020 distributes throughout the body,
  including across the normal blood-brain barrier
• No safety or toxicity concerns at doses
  considered 20X therapeutic dose level
• source of data AVI BioPharma, Inc.

24
WNV Treatment Trial 3 3rd Generation
Anti-sense Background

• AVI-4020-CL-01 Pilot Study in Summer/Fall 2003
• Total of 10 volunteers received at least one dose
  of AVI-4020
• 7 with active/recent/remote WNV disease
• 3 with recent viral illness
• No safety or toxicity concerns
• Source of data AVI BioPharma, Inc.

25
WNV Treatment Trial 3 3rd Generation
Anti-sense Background

• Emergency IND in June 2004
• MD request for active WNV neuroinvasive disease
  (polio-like syndrome) in June 2004
• AVI-4020 administered intravenously at 45 mg Q12
  hours x 5 days
• No safety or toxicity concerns at this dosage
  level
• AVI-4020 drug levels in CSF were determined
• 3 times higher than when 15 mg Q12 hrs
  administered
• Considered sufficient to interfere with WNV
  translation based on a cell free assay
• Dramatic resolution of meningitis and eventual
  full neurologic recovery within 2 months
• Source of data AVI BioPharma, Inc.

26
WNV Treatment Trial 3 3rd Generation
Anti-sense Contact Information

• Phone contact503-227-0554
• WNV response team 800-225-8101
• Dr. Peter OHanley, Sr. VP Clinical Development
• Desiree Hollemon, Director Clinical Operations
  (DHollemon_at_avibio.com)
• Janet Christensen, VP Quality Assurance and
  Regulatory Affairs
• http//www.clinicaltrials.gov/ct/show/NCT00091845
  

27
References

• Agarwal AG, Peterson LR. Human immunoglobulin as
  a treatment for West Nile virus infection. J
  Infect Dis. 2003 1881-4.
• Ben-Nathan D, Lustig S, Tam G, Robinzon S, Segal
  S. Rager-Zisman B. Prophylactic and therapeutic
  efficacy of human intravenous immunoglobulin in
  treating West Nile virus infection in mice. J
  Infect Dis. 2003 1885-12.
• Chowers M, Lang R, Nassar F, et al. Clinical
  characteristics of the West Nile fever outbreak,
  Israel, 2000. Emerg infect Dis. 2001 7675-678.
• Hamdan A, Green P, Mendelson E, Kramer MR, Pitlik
  S, Weinberger M. Possible benefit of intravenous
  immunoglobulin therapy in a lung transplant
  recipient with West Nile virus encephalitis.
  Transpl Infect Dis. 2002 4160-2.
• Interscience Conference on Antimicrobial Agents
  and Chemotherapy. Washington, DC, Oct-November
  2004
• Leyssen P, Drosten C, Paning M, et al.
  Interferons, interferon inducers, and
  interferon-ribavirin in treatment of
  flavivirus-induced encephalitis in mice.
  Antimicrob Agents Chemother. 2003 47 777-82.
• Nash, D, Mostashari F, Fine A, et al. The
  outbreak of West Nile virus infection in the New
  York City area in 1999. N Eng J Med. 2001
  3441807-1814.

28
References

• Pepperell C, Rau N, Krajden S, et al. West Nile
  virus infection in 2002 morbidity and mortality
  among patients admitted to hospital in
  southcentral Ontario. Can Med Asso J. 2003
  1681399-405.
•  
• Peterson L, Marfin A, Gubler D. West Nile virus.
  JAMA. 2003 290 524-528.
• Rahal JJ, Anderson J, Rosenberg C, Reagan T,
  Thompson LL. Effect of interferon-alpha2b therapy
  on St. Louis viral meningoencephalitis clinical
  and laboratory results of a pilot study. J Infect
  Dis. 2004 1901084-7.
• Sejvar J, Leis A, Stokic D, et al. Acute flaccid
  paralysis associated with West Nile virus
  infection. Emerg Infect Dis. 2003 9788-793.
• Tsai T, Popovici F, Cernescu C, Campbell G,
  Nedelcu N. West Nile encephalitis epidemic in
  southeastern Romania. Lancet. 1998 352767-771.
• Weiss D, Carr D, Kellachan J, et al. Clinical
  findings of West Nile virus infection in
  hospitalized patients, New York and New Jersey,
  2000. Emerg Infect Dis. 2001 7654-658.
•  

29
References

• Additional sources of information
• http//www.cdc.gov/ncidod/dvbid/westnile/index.htm
  
• Interferon study James Rahal
• IVIG study Penny Jester
• Anti-sense (AVI) study Janet Christensen