Two confirmed postmarketing PML cases have been identified in the NTZ-treated CD patient population from the FDA Adverse Event Reporting System (FAERS); see Appendix A. These cases are described below.
Case # 7888327 (MCN 2011BI011795, March 2011)
This is a confirmed case of NTZ-associated PML in a 31 year-old male with ileocolonic CD, which was also reported as a meeting abstract.29 Concomitant medications were oral
budesonide, hydrocortisone suppository, mesalamine, colestipol, loperamide, rifaxan, and
ciprofloxacin. Previous medications included methotrexate and two tumor necrosis factor (TNF) blocker (specific drugs and dates of exposure not reported). NTZ treatment started in May 2008 and the last infusion was in March 2011; 35 total infusions of NTZ were administered. The patient developed neurological symptoms (palinopsia and visual field defects) 2 weeks after his last NTZ infusion prompting evaluation and hospitalization. A brain MRI revealed a lesion suggestive of PML and the diagnosis was confirmed when CSF tested positive for JCV DNA. The patient underwent plasma exchange (PLEX), but developed immune reconstitution inflammatory syndrome (IRIS). Methylprednisolone was used for treatment of the IRIS. In addition to the PLEX, the patient also received mirtazapine and mefloquine for treatment of the PML. As of last follow-up report, the patient is disabled with persistent expressive and receptive aphasia, 2/5 strength and diminished sensation on the right side.
29 Etzel JP, Sohal K, Isaacs KL, et al. Progressive Multifocal Leukoencephalopathy with Plasma Exchange and Blockade of Immune Reconstitution Inflammatory Syndrome (IRIS) in a Patient with Crohn's Disease. Digestive Disease Week: abstr. Sa1219, 2012.
TAB 7 NATALIZUMAB EXPERIENCE
122 Case # 8913489 (MCN 2012BI051723, October 2012)
This is a confirmed case of NTZ-associated PML in a 52 year-old female with CD. No concomitant medications were reported. Prior immunosuppressants included
methotrexate, azathioprine, infliximab and adalimumab (dates of exposure not reported). NTZ treatment started at 300 mg IV monthly in November 2008 and the last infusion was in October 2012; 47 total infusions of NTZ were administered. Baseline testing in May 2012 was notable for positive anti-JCV antibodies, but a brain MRI was negative for any lesions suggestive for PML. Five months later in October 2012, the patient complained of neurologic symptoms (right sided weakness, increased falls and confusion). A brain MRI revealed a lesion suggestive of PML and the diagnosis was confirmed when CSF tested positive for JCV DNA. The patient underwent PLEX for the treatment of PML. She developed IRIS related to the PLEX and was treated with IV methylprednisolone. Upon last follow-up report in May 2013, the patient is alive and without any neurological sequelae.
In collaboration with the Division of Biometrics VII (DB7), the incidence and incidence rates (with corresponding 95% confidence intervals) of NTZ-associated PML for the CD patient population were calculated using the confirmed PML cases from FAERS and NTZ exposure data provided by Biogen Idec from January 14, 2008 (approval date for CD indication) through October 31, 2012.30 NTZ exposure data are obtained from the TOUCH prescribing program, which tracks all patients receiving NTZ. Table 2 provides estimated PML risk among NTZ- treated CD patients in the postmarket setting.
An analysis by the Division of Epidemiology II (DEPI II) looking at national NTZ sales data was not able to obtain patient exposure estimates.31 Furthermore, DEPI II’s analysis was not able to stratify by indication for Crohn’s disease due to a limited sample size. Due to these limitations, it was determined that the data from the TOUCH prescribing program would be the best estimate of patient exposure of NTZin the US for calculating incidence and incidence rates of NTZ- associated PML in the CD population.
Table 2: PML Risk Estimates with 95% Confidence Intervals for NTZ-treated Crohn's Disease Patients.
No. PML Cases Exposure Risk Measure
Incidence 2 1127 Patients 1.77* (0.2, 6.5)
Incidence Rate 2 1160 Patient Years 1.72** (0.2, 6.2) * Per 1000 Patients. Confidence interval computed by using an exact method based on the binomial distribution. ** Per 1000 Patient Years. Confidence interval computed by using an exact method based on the Poisson distribution.
The estimated incidence of PML for NTZ-treated CD patients is 1.77 per 1000 patients. The estimated incidence rate is 1.72 per 1000 patient years of exposure; in other words, if you exposed 500 patients to NTZ for an average of two years, you would expect to see 1.72 cases of PML.
30 Periodic Safety Update Report, Natalizumab/Tysabri. January 23, 2013. Biogen Idec Inc.
31 Montenegro S. (October 21, 2013 ). Drug Use Review -- Brief. Food and Drug Administration, Center for Drug Evaluation Research – Product name(s): Tysabri® (natalizumab), OSE RCM#(s): 2013-1921.
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Stratification of incidence estimates by risk factors is not feasible for the NTZ-treated CD patient population alone because the number of cases of PML (n=2) and exposure to NTZ (1,127
patients) in this population is limited. Furthermore, it is not clear that the 3 previously-
mentioned risk factors identified for the overall NTZ-treated patient population are applicable to the NTZ-treated CD patients because 1) the underlying disease (MS vs. CD) and prior
immunosuppressant use are different, and 2) even if the same 3 risk factors are relevant to the CD population their distributions may differ from those seen in the MS population.
Notwithstanding the limitations previously mentioned, this calculated incidence of 1.77 per 1000 CD patients (95% CI 0.2 – 6.5) is comparable to the cumulative PML incidence (independent of risk factors) of 2.63 per 1000 (95% CI 2.2 – 2.9) for the entire NTZ-treated population.27 Two cases of NTZ-associated PML occurring after 35 months of therapy suggests that duration of use of NTZ might be associated with the development of PML in patients with Crohn’s disease. However, the small number of cases renders a formal statistical analysis infeasible.