PMC7094807_01
PMC7094807_02
Overview of PML cases in the FDA Adverse Event Reporting System (FAERS). (A) Total PML cases reported in the FAERS database sub-grouped by the patient's underlying disease (see Methods). (B) Total drug-linked PML cases for the Leukemia/Lymphoma patients (top chart) and MS patients (bottom chart). The largest number of drug-linked PML cases in these disease groups were found for rituximab and natalizumab (Other drugs subgroup contains drugs linked to a small number of PML cases).
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FAERS data (Figure 1) calculated average of 179 natalizumab-associated PML cases per year (4-year average excluding high outlier year 2015), on an annual basis our 3-variant or 9-variant PML risk test panels would prevent 47-84 PML cases and 11-20 deaths. Figure 2B (bottom panel) also shows how we envision our PML genetic risk test could be implemented in the clinical setting, wherein patients testing positive for both the JCV antibody test and the genetic risk test would be strongly advised not to take natalizumab.
PMC7094807_03
PMC7094807_04
Overview of PML cases in the FDA Adverse Event Reporting System (FAERS). (A) Total PML cases reported in the FAERS database sub-grouped by the patient's underlying disease (see Methods). (B) Total drug-linked PML cases for the Leukemia/Lymphoma patients (top chart) and MS patients (bottom chart). The largest number of drug-linked PML cases in these disease groups were found for rituximab and natalizumab (Other drugs subgroup contains drugs linked to a small number of PML cases).
fneur-11-00186-g0001.jpg
PMC7094807_04_fneur-11-00186-g0001.jpg
F1
FAERS data (Figure 1) calculated average of 179 natalizumab-associated PML cases per year (4-year average excluding high outlier year 2015), on an annual basis our 3-variant or 9-variant PML risk test panels would prevent 47-84 PML cases and 11-20 deaths. Figure 2B (bottom panel) also shows how we envision our PML genetic risk test could be implemented in the clinical setting, wherein patients testing positive for both the JCV antibody test and the genetic risk test would be strongly advised not to take natalizumab.
MS-Natalizumab patient population (2014-2016) and predicted performance of a PML genetic risk test. (A) Number of MS patients (JCV-negative vs. JCV-positive) on natalizumab and the subset that developed PML are based on a summary by Schwab et al.. (B) Predicted impact of a PML genetic risk test is based on the population impact data reported in Table 4 (EUR MS, variants 1, 3, and 4). A suggested diagnostic decision process (bottom panel) is depicted for patients that test positive and/or negative on the JCV antibody test (currently used in natalizumab treatment decisions) and the proposed PML genetic risk test.
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Tonk et al., assuming a PML adverse event frequency for natalizumab of 1.3% (see Methods). To model the PML risk test performance in MS patients on natalizumab (see below), we used the JCV-negative and JCV-positive subgroups reported by Schwab et al. (Figure 2) for determining the number of MS cases that would be excluded from natalizumab therapy and the number of PML cases that could be prevented. The clinical impact that our 3-variant PML genetic risk test would have in the MS patient community considering natalizumab therapy is modeled in Figure 2. Table 2 of Schwab et al.) means 45,000 patients will be JCV-negative and 55,000 patients will be JCV-positive. The number of PML cases in the MS population is also depicted (Figure 2A, right chart), which predominantly occurs in the JCV-positive patient subgroup (418 cases vs. only 4 in JCV-negative patients). Figure 2B shows that adding our 3-variant PML risk test (Table 4) to the clinical decision process would exclude only 744 patients from natalizumab treatment but would prevent 109 PML cases in the subset of patients that are JCV-positive. FAERS data (Figure 1) calculated average of 179 natalizumab-associated PML cases per year (4-year average excluding high outlier year 2015), on an annual basis our 3-variant or 9-variant PML risk test panels would prevent 47-84 PML cases and 11-20 deaths. Figure 2B (bottom panel) also shows how we envision our PML genetic risk test could be implemented in the clinical setting, wherein patients testing positive for both the JCV antibody test and the genetic risk test would be strongly advised not to take natalizumab.