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What is on the horizon for flu treatment?
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The 2017-2018 influenza season in the United States was one of the most severe in the last decade and kept clinics, EDs and hospitals busy. The CDC recently classified it as a “high-severity” season that resulted in record hospitalization rates. Although vaccination is our first line of defense, it is most effective when it is a good match with the circulating strain. Unfortunately, vaccine efficacy for the 2017-2018 season was approximately 36% overall and only 25% against illness caused by influenza A(H3N2), the predominant strain. Because of low vaccine efficacy and a high number of patients with influenza, many patients sought treatment for their symptoms.
Neuraminidase inhibitors (NAIs) are the only agents recommended for treatment of influenza in the U.S. because most influenza strains are resistant to adamantanes. Since October 2017, the CDC has tested more than 4,600 influenza viruses for resistance to the NAIs. Rates of resistance were the highest for influenza A(H1N1) viruses, with 1% resistant to oseltamivir and peramivir. Zanamivir sensitivity has remained strong, with no reported resistant isolates discovered. Even though current rates of resistance to the NAIs are low, there is a sincere need for new medications to improve the treatment of influenza. One of the current problems with the NAIs is that their efficacy is diminished if treatment is delayed longer than 48 hours after the onset of symptoms. In addition, their effectiveness is still highly debated, highlighting the need for new, more effective treatments, especially for those at high risk of complications. There are several promising compounds currently under development (see Table).
Host cell-targeted therapy
There are two agents being studied for influenza treatment that specifically target the host cells that are vital for influenza replication. Nitazoxanide is a drug that is approved by the FDA for treatment of Cryptosporidium infections. However, it also has broad-spectrum antiviral activity, including activity against influenza viruses. After oral administration, nitazoxanide undergoes deacetylation in the blood to the active form tizoxanide, which interferes with the viral hemagglutinin assembly. Clinical trial results have demonstrated that nitazoxanide 600 mg twice daily, started within 48 hours, reduced symptom duration by approximately 36 hours. When used in combination with oseltamivir, synergistic activity has been demonstrated against influenza A viruses, including oseltamivir-resistant strains. Additional trials are currently underway.
DAS181 is a recombinant protein that has potent activity against influenza and other respiratory viruses such as human metapneumovirus and parainfluenza. It works by removing sialic acid receptors from the respiratory epithelium, which the influenza virus uses to enter the host cell. It is administered as an oral inhaled dry powder formulation that allows it to reach the upper and central respiratory tract but not the lower respiratory tract. Administration of DAS181 for 3 days has been shown to reduce viral shedding compared with placebo. Use for up to 7 days has been well-tolerated in a phase 1 trial in healthy subjects. However, respiratory adverse effects and the production of antibodies with neutralizing capability occurred when used for greater than 7 days. This will limit its use for longer durations and potentially for repeated courses of therapy.
Viral polymerase inhibitors
Pimodivir has received a fast track designation from the FDA because of its potential to address an unmet medical need. It prevents viral gene expression by a process known as “cap-snatching,” in which it targets the PB2 subunit of the viral polymerase and prevents it from binding the GTP cap structures on the host RNA. One drawback of this agent is that despite having potent influenza A activity, it lacks coverage for influenza B strains. The most important feature of this agent is that it has been shown to be effective if given up to 4 days after infection in a mouse model and was superior to oseltamivir in terms of efficacy. Pimodivir-resistant mutants have been seen in vitro but have remained sensitive to NAIs.
Baloxavir marboxil recently received preliminary approval in Japan for the treatment of influenza and has been granted priority review by the FDA. It is active against both influenza A and B viruses and has been shown to remain active against oseltamivir-resistant strains. Baloxavir marboxil is a novel, cap-dependent endonuclease inhibitor that blocks virus proliferation by inhibiting mRNA synthesis. A major advantage of this agent is that it is administered as a single dose of one pill, which will increase patient compliance. A single dose of baloxavir marboxil was shown in a phase 3 trial (CAPSTONE-1) to significantly reduce time to cessation of viral shedding compared with oseltamivir — 24 hours vs. 72 hours, respectively. Time to resolution of fever was also greatly reduced: 24.5 hours compared with 72 hours in those receiving oseltamivir.
Favipiravir is a purine nucleoside analog that is active against several RNA viruses by acting on the viral RNA-dependent RNA polymerase. It has been approved for use in Japan for treatment of influenza patients in a pandemic setting. In the United States, a phase 3 efficacy and safety trial for uncomplicated influenza in adults has been completed, but results have not been published. Favipiravir was shown to be synergistic when given with NAIs, and it has also shown improved survival in a murine model. The concern with this agent is that it has a risk for teratogenicity and embryotoxicity.
Monoclonal antibodies
There are several monoclonal antibodies currently under development for the treatment of influenza. Most of them target the viral hemagglutinin (HA) by binding to the conserved stalk portion of the HA molecule and preventing fusion of the virus with the host cell. However, there is one experimental antibody that targets the influenza A virus M2 protein, which prevents viral budding. So far, these agents have shown promise in terms of safety and efficacy, but most are still in phase 1 and 2 trials. Monoclonal antibodies are generally expensive agents, so their utility for prevention or treatment of seasonal influenza may be limited. However, they could be a valuable addition for patients at high risk of influenza-related complications.
Although it is not a novel agent, an IV formulation of the neuraminidase inhibitor zanamivir has been undergoing study as well. In a randomized trial, the clinical response to IV zanamivir was found to be not statistically different compared with oseltamivir treatment. Although inhaled zanamivir has been available for some time, the IV formulation would provide us with another agent in addition to IV peramivir for patients unable to take oral or inhaled medications.
The current data available for these new compounds are promising. Given the global burden that influenza has on patients, it is imperative to discover new agents that have a different mechanism of action than the NAIs and a low propensity to induce resistance. Some of these new agents have been shown to work synergistically with oseltamivir. Therefore, combination therapy for influenza may be seen in the future, which it is hoped will improve clinical efficacy in human trials. In addition to the experimental treatments for influenza, work is ongoing to develop more effective vaccines. A new National Institute of Allergy and Infectious Diseases-sponsored trial for a universal influenza vaccine has recently begun in the U.S. using the vaccine M-001. This vaccine contains antigenic peptide sequences shared among many different strains of influenza, which may provide protection against current and emerging strains. Although this is very exciting, there are still many questions that need to be answered before we will see a universal influenza vaccine come to market. Emerging treatments, along with new and improved vaccines against influenza, are desperately needed to prevent morbidity and mortality related to the illness.
- References:
- Garten R, et al. MMWR Morb Mortal Wkly Rep. 2018;doi:10.15585/mmwr.mm6722a4.
- Koszalka P, et al. Influenza Other Respir Viruses. 2017;doi:10.1111/irv.12446.
- Marty FM, et al. Lancet Respir Med. 2017;doi:10.1016/S2213-2600(16)30435-0.
- Shaw ML. ACS Infect Dis. 2017;doi:10.1021/acsinfecdis.7b00142.
- Sautto GA, et al. Virol J. 2018;doi:10.1186/s12985-017-0918-y.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS-AQ ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: JBrock@mercydesmoines.org.
Disclosure: Brock reports no relevant financial disclosures.