Inhibiting Viral Polymerase and Neuraminidase in Treating Influenza

(See the Major Article by Finberg et al on pages 1026–34.) The first neuraminidase inhibitors (NAIs), oseltamivir and zanamivir, were approved almost 2 decades ago for the treatment of influenza virus infections. NAIs are currently the only antiviral drugs clinical useful in the United States, as the circulating influenza A(H3N2), A(H1N1)pdm09 and B virus strains are no longer susceptible to adamantanes. Recently, other NAIs have been approved for clinical use, including intravenous peramivir and inhalational laninamivir (the latter only in Japan) [1]. Although these agents provide options for the management of patients infected with influenza, they have important limitations. As such, newer antivirals with different mechanisms of action are needed, particularly in treating high-risk patients and those with severe infections requiring hospital care. The NAIs have been shown in randomized, placebo-controlled trials to shorten illness and duration of viral shedding in ambulatory patients with milder infections [2, 3]. The greatest efficacy is provided with early NAI initiation after symptom onset, and the benefit is modest in most patients. A more recent meta-analysis had shown reduced risk of lower respiratory tract complications and admission to hospitals [4]. Controlled data in patients with more severe infections and in the hospitalized are emerging, as newer agents are developed [3, 5, 6]. Nonetheless, numerous observational studies have consistently reported improved outcomes in those who received NAI treatment [7, 8]. Despite their clinical utility, there are several limitations to treatments targeting the neuraminidase, which act by preventing release and spread of progeny virions. First, they need to be initiated as soon as possible after illness onset, as clinical efficacy declines rapidly with time. In ambulatory patients, there is little benefit if given after 2 days, and in the hospitalized, after about 4‒5 days of illness (with an estimated 20% increase in risk of adverse outcomes per day delay in starting treatment) [7, 8]. The wider therapeutic window in hospitalized patients likely is explainable by their longer duration of viral replication [5, 6, 8, 9]. Second, in some patients with severe pneumonitis, the virologic response can be slow, and continued clinical progression may occur despite NAI initiation [9]. Thirdly, resistance to oseltamivir (eg, via the H275Y mutation) has been shown to emerge in some patients (eg, young children, immunocompromised hosts, half-dose prophylaxis) or occasionally without drug exposure (eg, 2007/2008 seasonal H1N1 outbreak). Treatment options for these resistant variants are very limited [1]. In this issue of the Journal of Infectious Diseases, the results of a phase 2b trial of pimodivir (JNJ-63623872, formerly known as VX-787), a compound that belongs to a new class of antiviral, the polymerase inhibitors, are reported by Finberg et al [10]. Pimodivir blocks the PB2 subunit of influenza A viruses, which binds to cellular capped RNAs as part of the “cap snatching” process, thus inhibiting virus replication. In vitro, it has been shown to be active against a diverse panel of influenza A virus strains (eg, H3N2, H1N1pdm09, H7N9, H5N1), as well as those with reduced susceptibility to NAIs. It is not active against influenza B viruses [11–13]. In this double-blind study, adults confirmed with acute uncomplicated influenza A infections (n = 223, H3N2 or H1N1pdm09) were randomized to receive placebo, pimodivir 300 mg, pimodivir 600 mg, or combination of pimodivir 600 mg and oseltamivir, all given twice daily for 5 days. It was found that when compared with placebo, pimodivir-treated patients had significantly reduced viral RNA load and infectious virus titer over time (indicated by lower area under the curve [AUC] over 7 days). Results on duration of viral shedding were similar. Greater efficacy was noted with the 600-mg regimen, indicating a dose-dependent relationship. Notably, viral load reduction was found to be greatest when combined with oseltamivir, and fewer cases of on- or posttreatment PB2 substitution were identified (1 versus 10). However, no significant clinical benefit was reported, which was attributed to insufficient statistical power as a result of early trial termination when a predefined virologic endpoint was met. Pimodivir was generally well tolerated, and the most common adverse events were mild or moderate diarrhea. Reversible liver enzyme elevation and cytopenia were also reported. The results of this trial show promising antiviral efficacy of pimodivir against clinical influenza infections. Whether this will translate into clinical benefits (eg, shortening duration of illness, reduction in complications and hospitalizations) will require confirmation in future studies. Other polymerase inhibitors, such as favipiravir (formerly T-705, inhibits viral RNA-dependent RNA polymerase of influenza A, B, and C viruses), and baloxavir (formerly S-033188, inhibits influenza A and B virus replication by targeting the cap-dependent endonuclease) are entering late-stage clinical development. Preliminary data from phase 2 and 3 trials suggest antiviral and clinical efficacies of these compounds (NCT02026349, NCT02008344; NCT02954354) [13–15]. The current study did not compare the relative potency of pimodivir to oseltamivir, as oseltamivir monotherapy was not included as a study arm. In a mouse model, it was shown that the polymerase inhibitor may result in a greater viral titer reduction in lungs than oseltamivir; moreover, protection from lethal challenge can be shown even when treatment was administered 96 hours postinfection [11]. Further study on the use of polymerase inhibitors in severe influenza infections with high virus burden and in those with advanced diseases are warranted. Importantly, because these new agents utilize mechanisms of action different from the NAIs, they are predicted to be active against NAI-resistant strains of influenza [1, 11, 13–15]. In addition, the Finberg et al study provides a glimpse into the use of combination antiviral treatment to target different stages of the virus replication cycle [10]. The pimodivir-oseltamivir combination was associated with a significantly greater degree of viral load reduction and earlier cessation of viral shedding compared to that observed with pimodivir monotherapy. Such results are consistent with recent in vitro findings of possible synergism between polymerase inhibitors and neuraminidase inhibitors [11–14, 16]. Whether enhanced viral inhibition can result in faster clinical resolution and better outcome will require further study; notably, a recent trial on oseltamivir-ribavirin-amantadine versus oseltamivir alone did not demonstrate clinical advantage despite modest benefit in viral clearance on day 3 [17]. Research on various combinations of polymerase and neuraminidase inhibitors have been proposed; in addition to their potential to treat severe, advanced diseases, the combination approach may minimize the risk of resistance emergence to both classes of agents, as demonstrated in prior studies combining NAIs and adamantanes [17–19]. The results of the Finberg et al study[10], showing fewer cases with resistance-implicated PB2 substitutions posttreatment in the combination arm, encourages additional studies on this approach. The rapid emergence of genetic variants during exposure to polymerase inhibitors should warrant particular attention. Unlike NAI resistance, where there is a working definition proposed by the World Health Organization (10‒100 and >100-fold increase in half maximal inhibitory concentration [IC50] values over corresponding reference strains for reduced inhibition and highly reduced inhibition, respectively) [1, 20], none exists currently for the polymerase inhibitors. Studies to investigate their clinical significance (eg, association with more prolonged symptoms or longer duration of viral shedding), as well as their “fitness” in replication and transmission, are urgently indicated [21]. One of the many challenges in conducting trials on influenza therapeutics is the lack of a validated study endpoint [22]. Virologic endpoints (eg, reduction of viral load or titer over time, cessation of viral shedding) are important as they indicate antiviral efficacy; however, there are limited data to support a precise correlation with clinical progression and outcomes [23]. Host responses likely play a major role in the clinical presentation; and it is known that low-level viral shedding may persist despite clinical recovery. In addition, as viral clearance occurs more quickly in the upper than in the lower respiratory tract in those with influenza pneumonitis [1, 9], the sampling site could confound findings. Because polymerase chain reaction (PCR) detects a mixed of infectious viruses and noninfectious RNA fragments, current culture methods are too insensitive, and few subjects have detectable virus beyond day 3 [1, 3, 5, 6, 17]. Further research on newer techniques for monitoring the virologic response and their relationship with clinical recovery is indicated. Current Food and Drug Administration (FDA) guidance advocates for the use of clinical endpoints that measure how a patient feels, functions, or survives. Several approaches to measure symptom intensities have been developed, but validation consistent with FDA guidance for industry has been limited. Recent trials based on time to symptom alleviation (with variable definitions) seem to provide reproducible results when studying ambulatory patients with mild seasonal influenza [3]. In hospitalized patients, it is even more difficult because of their protean manifestations and heterogeneous outcomes. Composite endpoints, such as time to normalization of vital signs or respiratory status, and ordinal scale outcomes, have been used in recent trials to indicate clinical recovery, and the findings are encouraging [3, 17, 24]. Further work is needed to identify and validate endpoints for use in influenza antiviral trials. In this study, a virologic endpoint was useful in demonstrating the proof-of-concept that a polymerase inhibitor has antiviral efficacy in humans, but led to early study termination without sufficient power to show clinical efficacy, highlighting the challenges ahead. In summary, the article by Finberg et al demonstrates the antiviral efficacy of a novel polymerase inhibitor in clinical influenza infections, as well as possible synergistic effects when combined with an NAI [10]. Its clinical benefit and risk of resistance require further investigation. Polymerase inhibitors may prove to have important roles in treating severe influenza, as well as infections caused by NAI-resistant viruses. Potential conflicts of interest. N. L. has received honoraria for consultancy work and travel support to meetings from Shionogi Ltd., Janssen Pharmaceuticals Inc., Visterra Ltd., hVIVO Ltd., and Seqirus Inc. M. I. has received research support, paid to Northwestern University, from Emergent BioScience, Gilead, Janssen, and Shire; he has received honoraria for consultancy work from Celltrion, Genentech/Roche, Janssen, Toyama/MediVector, Seqirus, Shionogi, and VirBio; he was a paid member of a DSMB for GlaxoSmithKlein and Shionogi. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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