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: <10 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 >18 years of age Patients with evidence of encephalitis/myelitis OR at high risk for development of encephalitis/myelitis (immunosuppression, age >40-50 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 1:1 treatment vs placebo IVIG 3 arms (3:1:1) Israeli IVIG Standard IVIG Placebo 3rd generation anti-sense 4:1 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 body’s host defenses (anti-viral replication has also been proposed as mechanism of action) *Antimicrobial Agents Chemother 2003;47:777

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 N=15 Rx with Interferon alpha-2b x 2 weeks N=8 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, 190:1084-7 **44th ICAAC presentation, Washington, Nov 04

18. West Nile treatment trial #1:Interferon 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@nyp.org) Wehbeh Wehbeh (wew9004@nyp.org) phone: (718) 670-1525 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 > 18 years with WNV-related encephalitis 3 groups: (3:1:1) 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 (205) 934-2424 (lriser@peds.uab.edu) Penny Jester, CASG Project Manager, University of Alabama (205) 996-7800 (pjester@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 contact:503-227-0554 WNV response team: 800-225-8101 Dr. Peter O’Hanley, Sr. VP Clinical Development Desiree Hollemon, Director Clinical Operations (DHollemon@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; 188:1-4. 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; 188:5-12. Chowers M, Lang R, Nassar F, et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg infect Dis. 2001; 7:675-678. 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; 4:160-2. 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; 344:1807-1814.

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; 168:1399-405.   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; 190:1084-7. Sejvar J, Leis A, Stokic D, et al. Acute flaccid paralysis associated with West Nile virus infection. Emerg Infect Dis. 2003; 9:788-793. Tsai T, Popovici F, Cernescu C, Campbell G, Nedelcu N. West Nile encephalitis epidemic in southeastern Romania. Lancet. 1998; 352:767-771. 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; 7:654-658.  

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