Comparing Common Therapies in Polycythemia Vera (PV): A Disproportionality Analysis in the FDA Adverse Event Reporting System (FAERS) Database

Background:

Prior to the approval of ropeginterferon alfa-2b-njft (ropeginterferon) in November 2021, the alternatives to hydroxyurea for the treatment of polycythemia vera (PV) included Janus Kinase inhibitors (JAKi) and older versions of recombinant interferon-alpha (rIFNα). As ropeginterferon and the JAKi ruxolitinib are the only FDA approved medications for the treatment of PV, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess reporting rates for adverse events (AEs) of both FDA-approved and non-FDA approved rIFNα and JAKi agents.

Methods:

AE data for ropeginterferon, peginterferon alfa-2a, ruxolitinib, and pacritinib in PV-treated patients were obtained from FAERS reports from November 1, 2021, through March 31, 2023. AEs were recorded using preferred terms (PTs) and primary system organ classes (SOCs) from the Medical Dictionary for Regulatory Activities (MedDRA). Serious non-fatal AEs (SAEs) were defined as AEs requiring hospitalization, life-threatening, resulting in disability, congenital anomaly, or otherwise medically significant. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using R v4.2.3 Statistical Software. The RORs were used to detect disproportional reporting rates for non-serious AEs, SAEs, and fatal AEs as well as SOC-specific reporting rates. A reporting signal was considered significant when the ROR 95% CI lower limit was greater than one.

Results:

SOC-specific RORs for the assessed treatments are summarized in Table 1. RORs by AE seriousness are displayed in Figure 1. Ropeginterferon had the only non-serious AE significant ROR (ROR = 5.37; 95% CI: 3.63 - 7.94). The two highest SOC-specific RORs for ropeginterferon were “Medical and Surgical Procedures” (ROR = 15.32; 95% CI: 1.88 - 124.67) and “Social Circumstances” (ROR = 6.30; 95% CI: 2.66 - 14.94).

Peginterferon alfa-2a had the highest SAE reporting odds (ROR = 5.68; 95% CI: 3.03 - 10.6). The highest SOC RORs for peginterferon alfa-2a were “Hepatobiliary Disorders” (ROR = 16.35; 95% CI: 4.86 - 55.01) and “Immune System Disorders” (ROR = 5.11; 95% CI: 1.49 - 17.48).

Ruxolitinib was the only agent assessed to have significant reporting signals for both SAEs (ROR = 1.93; 95% CI: 1.43 - 2.61) and fatal AEs (ROR = 9.86; 95% CI: 3.62 - 26.82) The highest SOC RORs for ruxolitinib were “Neoplasms Benign, Malignant, and Unspecified” (ROR = 7.96; 95% CI = 3.47 - 18.27) and “Product Issues” (ROR = 3.85; 95% CI: 2.42 - 6.12).

Conclusions:

This study examined FAERS reports to detect disproportional reporting odds of drug-associated AEs severity and SOCs in four PV treatments: ropeginterferon, ruxolitinib, interferon alfa-2a, and pacritinib. Ropeginterferon had a significant ROR for non-serious AEs. Peginterferon alfa-2a demonstrated a significant ROR for SAEs. Ruxolitinib had both significant SAE and fatal AE RORs.

The highest SOC-specific RORs for ropeginterferon were in the non-specific categories of “Medical and Surgical Procedures” and “Social Circumstances.” Peginterferon alfa-2a had significant SOC signals for “Hepatobiliary Disorders” and “Immune System Disorders,” which are AE categories also reported in the prescribing information for peginterferon alfa-2a. “Neoplasms Benign, Malignant, and Unspecified” was the highest SOC ROR for ruxolitinib and may potentially relate to the association of treatment with secondary malignancies.

Limitations include a lack of adjustments for multiplicity due to the exploratory nature of the analysis. AEs reports to FAERS may not be treatment related. In addition, publicity or FDA approvals may disproportionately affect reporting rates for ropeginterferon (FDA-approved in 2021) or ruxolitinib (approved for PV in 2014). FAERS may also not include representative AE reports as healthcare provider and patient submissions are both postmarketing and voluntary. Fatal events during clinical trials were reported to the FDA (including ropeginterferon) but are not reflected in FAERS. Therefore, FAERS data may not represent the true incidence of AEs. Reporting signals for any treatments or any causal relationship should be confirmed by assessing future AE reporting trends, electronic health records analysis, or prospective clinical trials.