RRP Task Force Activities RRP Focus Group 2007

1. RRP Task Force ActivitiesRRP Focus Group 2007 Craig Derkay, MD Professor and Vice-Chairman Otolaryngology and Pediatrics Eastern Virginia Medical School

2. RRP Task Force • Multi-disciplinary group that meets twice yearly (September and May) in conjunction with the AAO and COSM • No further funding from CDC to continue registry • Coordination of research efforts and assistance to investigators to disseminate information and recruit interested centers and patients • Formulated statement on Public Health Infection concerns for children with RRP • Formulated statement on Cidofovir safety and use • Tackling statement on HPV typing • Working with Merck and Sanofi to develop prospective investigation of role of the vaccine in reducing the incidence of RRP and treatment for existing patients

3. Post-Licensing Suggestionsfor RRP Vaccine Trials • Establish the anti-HPV 6 and anti-HPV 11 antibody levels in cohort of actively treated RRP patients to determine who might benefit from therapeutic administration of vaccine • Vaccinate a cohort of children (girls and boys) currently in remission and follow for several years • Begin surveillance study of new-onset RRP and compare over time the incidence and prevalence in a community • Attempt a therapeutic trial, perhaps in conjunction with artemisinin or another cytotoxic drug

4. Children and partners of patients with RRP have no evidence of the disease during long-term observationGerein V, Intl J Ped Oto 2006;70; 2061-2066 • 15 year multi-center, prospective and retrospective German and Russian study to investigate whether children and partners of RRP patients develop the disease and whether there is an impact of pregnancy on the disease • Total of 54 patients with 50 offspring • All children born to RRP patients were healthy and RRP was never diagnosed • None of the sexual partners of RRP patients has developed the disease

5. Children and partners of patients with RRP have no evidence of the disease during long-term observationGerein V, Intl J Ped Oto 2006;70; 2061-2066 • All pregnant women with HPV 11 had excessive growth of papillomas while only 17% of HPV 6 women demonstrated this (p<.0001) • Conclusions: Patients with RRP are able to have healthy children regardless of the stage of their disease. The sexual partners of RRP patients do not appear to be at risk of developing RRP. Pregnancy has a negative impact on the course of RRP that is worse with HPV 11.

6. Toxicity issues with Cidofovir • Received expedited approval by FDA under HIV/AIDS fast-track rules • Only approved for use to treat CMV-retinitis in AIDS patients • Animal studies worrisome regarding potential for carcinogenicity • Plasma assays after local injection produce levels at-risk for nephrotoxicity • Use outside of clinical protocols becoming widespread without systematic evaluation of adverse events

7. A case of progressive dysplasia concomitant with intralesional Cidofovir administration for RRPWermer, Smith, Annals Jan 2006 • Case report of 28 year-old non-smoker with RRP who experienced progressive and worsening dysplasia while being treated with intra-lesional Cidofovir (5mg/cc x 3.5cc) on 3 occasions over 27 months • Raises concern over off-label use

8. Cidofovir • Black Box warning: Annals 2005;114;834-5Potent carcinogen in ratsIntra-lesional injections may achieve local and systemic levels high enough to induce toxicitiesCase reports showing progression to severe dysplasiaLiability all on the shoulders of the physicianInformed consent is the key

9. Cidofovir for RRP: A re-assessment of risksRRP Task Force consensus statement on CidofovirDerkay et al, Int J Ped Oto 2005;69;1465-1467 • Given the promising results reported in pediatric and adult patients, cidofovir should be routinely presented as a treatment option in moderately-to-severely afflicted RRP patients. i.e.; those patients whose disease is not improving on surgical therapy alone or in conjunction with less potentially morbid adjuvant measures and/or requiring surgical intervention greater than 3 times a year. • With appropriate consent, cidofovir therapy should be a viable option in patents whose disease severity is resulting in a need for frequent surgery, worsening airway compromise or severely impaired communication or those who otherwise may be considered candidates for tracheotomy

10. Cidofovir for RRP: A re-assessment of risksRRP Task Force consensus statement on CidofovirDerkay et al, Int J Ped Oto Oct 2005 Patients with more mild disease, particularly children, should be discouraged in most cases from seeking treatment with cidofovir, until a better understanding of the long-term implications of the use of this drug have been established. With appropriate informed consent, cidofovir could still be utilized on a case-by-case basis, at the discretion of the prescribing physician, for the more mildly affected patient.

11. Cidofovir for RRP: A re-assessment of risksRRP Task Force consensus statement on CidofovirDerkay et al, Int J Ped Oto Oct 2005 As with all surgical procedures, informed consent should be obtained and documented in the patient's record. At a minimum, this should include a frank discussion of the nephrotoxic and carcinogenic potential of this drug.

12. Cidofovir for RRP: A re-assessment of risksRRP Task Force consensus statement on CidofovirDerkay et al, Int J Ped Oto Oct 2005 Adverse responses, particularly evidence of dysplasia or malignant transformation to squamous cell carcinoma, either locally or remotely, should be reported simultaneously to the FDA (form 3500 or 3500A) and to the RRP Task Force through email communication with its Chairman, Craig Derkay, MD (craig.derkay@chkd.org)

13. Role for HPV Testing • Formulating a statement • Awaiting approval of commercially available testing

14. Reasons for HPV Sub-typing • Prognosis for individual patients at time of diagnosis • Plan more frequent surgical interventions • Aggressive airway surveillance • CT scans of chest at intervals • Risk of malignancy (HPV 16,18, 11?) • Clearly, in the pediatric airway, HPV 11 is high risk

15. HPV subtypes causing RRP: 6,11 (16,18 rarely) • Previous studies, most non prospective, suggest HPV 11 has more aggressive course • Rimmel et al;Prognosis of viral subtyping.Laryngoscope, 1997 • HPV-11 worse prognosis, frequency, tracheal spread • Rabah et al; HPV subtype 11 more aggressive than HPV 6.Archived parafin specimens.Pediatric & Developmental Pathology, 2001 • Maloney et al; Viral loads in HPV 6 and 11, antibody response and clinical course Archives Oto. July 2006 • Viral load constant for 6 and 11. only antibody response in type 11 patients. Worse clinical course for type 11 • Wiatrak et al; 10 year prospective analysis of viral subtypes.Laryngoscope, 2004.

16. Longitudinal measures of HPV 6 and 11 viral loads and antibody response in children with RRPMaloney, Unger, Reeves et al, Arch OTOHNS 2006;132;711-715 • Longitudinal pilot study of 15 children at Egleston Children’s with RRP to measure viral loads of HPV 6 and 11 and associated clinical severity • 4 had HPV 6; 4 HPV 11 and 7 had mixed 6/11 • Viral loads were stable over time • HPV 11 was significantly associated with more annual surgical procedures (p=.02) • Only 3/15 children had detectable antibodies against viral-like particles (all HPV 11) • Conclude: Little need to repeat HPV typing over time

17. Age of child, more than HPV type, is associated with clinical course in RRPBuchinsky FJ, 2007 in press • Interim analysis of 118 children with RRP enrolled in gene-mapping study • Clinical course analyzed with respect to HPV type and age of the patient • HPV 11 patients were 4x more likely to run an aggressive course • Age of patient at time of surgery or age at the time of diagnosis were more closely associated with overall clinical course than HPV type.

18. RRP Viral Typing • Gerein V. Et al: Incidence, age at onset, and potential reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years experience.Otolaryngology - Head & Neck Surgery. 132(3):392-4, 2005 Mar.Univ. of Mainz, Germany • 42 cases of SEVERE RRP, failed IFN therapy • ALL pt’s with pulmonary spread had HPV type 11 • 5 of the hpv 11 pt’s developed cancer (4 of 5 smokers) • The results of long-term follow-up in RRP patients with HPV11 underline the necessity of reanalyzing the current therapy

19. RRP Viral Typing • Reidy, P. Et al: Wayne St. University , Detroit, MI • Integration of human papillomavirus type 11 in recurrent respiratory papilloma-associated cancer.Source Laryngoscope. 114(11):1906-9, 2004 Nov. • Increased incidence of HPV type 11 in laryngeal CA pt’s with prior history of RRP

20. Brian Wiatrak’s Triolgic Thesis Summary Wiatrak et al; Laryngoscope. 2004 Nov;114 (11 Pt 2 Suppl 104):1-23 • 73 patients, 10 years, standard RRP staging system • HPV-11 more likely to: • Have Higher severity scores • More frequent surgery • Require adjuvant medical Rx. • Have higher incidence of tracheal dz. • Require tracheotomy • Develop pulmonary dz.

21. HPV Sub-TypingDigene® • The Digene® HPV Test*, using Hybrid Capture® 2 (hc2) technology, is the only FDA–approved HPV DNA test and collectively detects the 13 clinically–relevant high–risk HPV types. • The Digene HPV Test is a signal–amplified, nucleic acid test that provides standardized, objective results upon which healthcare providers may rely on to accurately assess patient risk for cervical intraepithelial neoplasia (CIN) and cancer. • The Digene HPV Test is the only FDA–approved HPV test for: • Primary screening, in conjunction with a Pap, of women age 30 years and older; and • Triage of women of any age with ASC–US Pap results.

22. High–risk type 16,18,31,33,35,39,45,51,52,56,58,59,68 Low-risk type 6,11,42,43,44 HPV Sub-Typing Digene® HPV Test

23. AMPLICOR® HPV testRoche Diagnostics • PCR- based HPV screening test • Identifies 13 high risk types • 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 • Therefore, HPV types 6 and 11 are termed low-risk (LR) HPV types, and HPV types involved in carcinogenesis (such as types 16 and 18) are termed high-risk (HR) HPV types. • Comparison of Two Commercial Assays for Detection of Human Papillomavirus (HPV) in Cervical Scrape Specimens 2005Maaike A. P. C. van Ham et al. Journal of Clinical Microbiology, June 2005, p. 2662-2667

24. Linear Array KitRoche Diagnostics • PCR-based linear array HPV product • Amplification of target DNA by PCR and Hybridization techniques • The linear array identifies 37 HPV genotypes, including all high- and low-risk genotypes. • Provides specific subtype (genotype) information • Currently available as research tool only • Insurance reimbursement issues • Plan is to make commercially available in the future (2007?)This is what we are waiting for!

25. Celebrex • Study funded by NIH. • DSMB group established with first meeting in September. • IND being prepared for FDA Awaiting word from Pfizer for inclusion of children in the protocol • Celebrex has been approved for use in children >2 years with rheumatoid arthritis (protocol will allow children >4 years) • Pilot data: 3/3 patients have achieved remission in 3, 6 and 9 months with 1 year of follow-up. All 3 had severe disease and one had tracheal involvement!