New therapeutic measure to combat influenza

Mechanism of action of new antiviral agent

Note from Dr Lee

Traditional anti-influenza drugs have been comprised of 2 groups: neuraminidase inhibitors and M2 ion channel inhibitors (aka, adamantanes). Now the US Food and Drug Administration (FDA) has approved (October 24, 2018) the use of a new drug for influenza with a novel mechanism of action. Known as baloxavir marboxil (Xofluza; Genentech USA Inc., San Francisco, California), this new drug targets the cap-dependent endonuclease of influenza viruses and is being introduced because of concerns for resistance to current available drugs.¹

Previous medications that target the influenza virus proteins included adamantanes, namely amantadine and rimantadine, and neuraminidase inhibitors, which include oseltamivir and zanamivir. Adamantanes, whose mechanism of action targets the M2 ion channel, prevent replication of influenza A viruses only. Neuraminidase inhibitors, effective against both influenza A and B viruses, prevent release of the progeny influenza virus from infected host cells.2 Recommendations no longer support the use of adamantanes as there has already been largely recognized resistance against these drugs and they only have activity against influenza A.^1,3,4

Neuraminidase inhibitors have been used widely in patients for active influenza virus infection and for chemoprophylaxis. The Centers for Disease Control and Prevention (CDC) currently recommends use of oseltamivir, in particular, for treatment of influenza in pa patients of all ages and for chemoprophylaxis for children and adults aged 3 months and older.⁵ Zanamivir is only available in an inhaled dosage form and is used for treatment of children and adults, aged 7 years and older. Unfortunately, emergence of antiviral resistance to this group of drugs has led to growing concerns with continued use of this drug class.³

Early clinical trials with oseltamivir revealed emergence of resistance up to 4% in adults who received treatment during seasonal influenza. Spread of these resistant strains showed potential of enhanced viral replication fitness that was not seen before 2007, whereas the neuraminidase inhibitor-resistant strains had previously compromised replication fitness.¹ The World Health Organization (WHO) declared an influenza pandemic on June 11, 2009, and during that time tested more than 27,000 H1N1 viruses for neuraminidase resistance and found that 447 were oseltamivir resistant. The prevalence of this resistance has continued to grow.¹

This increase in resistance has led to the study of other proteins within the influenza virus that can be targets of antiviral agents. The influenza virus RNA-dependent RNA polymerase complex is composed of 3 protein subunits: polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA).^3,6 The acid polymerase protein in influenza virus functions to cleave the mRNA caps and initiate mRNA transcription.⁶ In 2016, Jones and colleagues published on RO-7, an endonuclease inhibitor found to inhibit influenza virus replication in vitro in several strains of influenza A (H1N1, H3N2) and influenza B (H5N1, H7N9, H9N2).

What’s different about baloxavir?

Baloxavir is a selective inhibitor of cap-dependent endonucleases. It first received global approval on February 23, 2018, in Japan for influenza A and B infections in otherwise healthy adults and children.⁷ It has in vivo and in vitro activity against oseltamivir-resistant strains with demonstrated synergism when combined with neuraminidase inhibitors.^3,7 The pro-drug S-033188 undergoes hydrolysis to active form S-033447, which has a peak concentration within 4 hours as well as a large volume of distribution.⁷ It is metabolized by UGT 1A3 (major) and CYP3A (minor) with biliary excretion. Its half-life is up to 80 hours, compared with oseltamivir, the active form of which has a half-life of at most 10 hours.^7-9

The CAPSTONE trial was a randomized, double-blind, placebo and active-controlled phase III trial with 1436 (1064 were included in intention-to-treat infected population) adolescents and adults aged 12 to 64 years with uncomplicated influenza A or B and symptoms for fewer than 48 hours.³ Patients in the phase III trial were from the United States and Japan, and were enrolled from December 2016 to March 2017. The trial found that those treated with baloxavir had a shorter time to alleviation of symptoms compared with placebo (53.7 hours vs 80.2 hours, respectively; P<0.0001). The trial also found that the time to cessation of viral shedding was decreased when compared with oseltamivir and a placebo (baloxavir group, 24 hours, vs placebo group, 96 hours, P<0.0001; and vs oseltamivir group, 72 hours, P<0.0001).^3,10 Time to resolution of fever also was shorter with baloxavir than the placebo group (24.5 hours vs 42 hours, respectively; P<0.001).³

In the study, influenza A (H3N2) accounted for 84.8% to 88.1% of infections in the 3 groups, and 77.2% of the patients were enrolled from Japan.³ When looking at adverse events reported in more than 1% of patients and believed to be related to the trial regimen, the most frequent adverse event was diarrhea occurring in 1.8% of patients in the baloxavir group.³ There were no adverse events that led to discontinuation of the trial that were believed to be related to the trial medication. The only 2 serious adverse events reported in the baloxavir group were inguinal hernia and aseptic meningitis.^3,7

Recommendations

Currently, the FDA is recommending use of this medication in patients aged 12 years and older with symptoms for no more than 48 hours. The FDA recommends administration without dairy products, calcium-fortified beverages, polyvalent cation containing laxatives, or antacids. Baloxavir is currently available as 20-mg and 40-mg oral tablets as a single-dose regimen; 40 mg for those weighing 40 kg to less than 80 kg, and 80 mg for those weighing greater than 80 kg.⁸ One advantage of single dosing would be increased likelihood of patient adherence to medication regimen completion, especially in the outpatient setting. Similar to its predecessor oseltamivir, baloxavir is currently only recommended in uncomplicated infections as the trials so far have only tested the medication in this population. Further studies will be needed to understand better how to apply the use of baloxavir in the inpatient setting and with more complicated clinical presentations.^3,8

Although it is not currently advised, and the studies are limited, there is a potential for synergism between oseltamivir with baloxavir. The agents work with completely different mechanisms and so far there are in vitro as well as murine studies that support their use together in humans.¹¹ One small study with 18 healthy adults in Japan did explore this and concluded that there was evidence of synergism between the 2 agents in humans. The authors supported the use of both agents with no dose adjustment as deemed necessary by healthcare providers.¹² This could be considered in more complicated or severe cases of influenza infection. However, the study was small and there is very little data that continue to support this, and no official recommendations have been provided as yet.

Further studies are underway to explore other drugs targeting the polymerase complex. However, even with these new drugs being explored, mutations leading to decreased viral susceptibility to antivirals can occur. Currently, there is a known mutation to baloxavir, although the known mutation leads to a virus with decreased ability to replicate.³ Still, while new drugs continue to be investigated, primary prevention with vaccination is currently the best way to prevent serious influenza infection as well as influenza epidemics and pandemics. Patients and providers alike should be encouraged to obtain their influenza vaccine at the early start of each season.