Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses that affect the respiratory tract. There are four types of influenza viruses: types A, B, C, and D. Types A and B are responsible for seasonal flu epidemics that occur almost every winter and can cause severe illness and life-threatening complications in some people. Influenza virus particles are enveloped and contain segmented RNA genomes. Influenza spreads around the world in seasonal epidemics and pandemics, resulting in about three to five million cases of severe illness and about 290,000 to 650,000 respiratory deaths per year globally.
Existing Anti-Influenza Drugs
There are currently four categories of approved anti-influenza drugs that include M2 inhibitors, neuraminidase inhibitors, poly(ADP-ribose)polymerase inhibitors and the triple combination. M2 inhibitors such as amantadine and rimantadine target the M2 ion channel of influenza A viruses to prevent virus uncoating inside host cells. However, widespread resistance to M2 inhibitors has emerged and limited their effectiveness. Neuraminidase inhibitors including oseltamivir, zanamivir, and peramivir are the most commonly prescribed influenza antivirals.
They inhibit influenza neuraminidase activity to interfere with virus spread. Clinical trials have established that neuraminidase inhibitors can reduce symptom duration if given early in infection. Poly(ADP-ribose)polymerase inhibitors like baloxavir marboxil suppress influenza virus replication by targeting the viral cap-dependent endonuclease. The triple combination of oseltamivir, baloxavir marboxil, and probenecid demonstrated synergistic anti-influenza activity in animal models and is under clinical evaluation.
Limitations of Current Therapies
Despite the availability of approved Influenza Therapeutics, therapy for influenza virus infections still suffers from certain limitations. Firstly, increasing resistance to the M2 inhibitors has eliminated them as front-line therapy options. Resistance to neuraminidase inhibitors has also begun emerging, though remains relatively low at present. Secondly, treatment efficacy of antivirals is reduced when therapy is initiated beyond 48 hours of symptom onset. This narrow treatment window poses difficulties especially for vulnerable populations that seek medical care later in the course of disease. A third major issue is toxicity concerns for baloxavir marboxil which can cause abnormal liver function in some recipients. Finally, treatment of severe influenza often requires hospitalization and supportive care like respiratory support and fluid management in addition to antivirals. Development of broadly effective therapeutics with improved safety remains an unmet need.
Novel Anti-Influenza Drug Candidates
Given the limitations of currently approved drugs, multiple innovative therapeutic strategies are under active investigation. RNA interference or RNAi-based antivirals like ALN-RSV01 that target conserved influenza genes show promise as one pan-influenza approach. Small interfering RNAs guided by viral RNA secondary structures could achieve broad specificity. Another category includes virus entry inhibitors like DAS181 that function by cleaving sialic acid receptors on respiratory epithelial cells. This denies influenza virus attachment and prevents infection completely. A third approach explores enhancing host immunity with recombinant versions of viral sensors like RIG-I to stimulate robust interferon signaling pathways upon virus recognition. Broad-spectrum antivirals targeting viral RNA-dependent RNA polymerase or cap-snatching machinery are also under preclinical assessment given the conserved nature of these processes. Finally, combination therapy regimens with dissimilar mechanisms may delay resistance and maximize treatment benefits. These novel strategies warrant further evaluation as potential influenza therapeutics with pan-influenza activity and improved safety profiles.
Pipeline Candidates Entering Clinical Stages
While basic research continues to explore new targets and concepts, some candidates have now advanced to clinical testing. Laninamivir octanoate is a long-acting neuraminidase inhibitor administered via inhalation that achieved marketing approval in Japan in 2010 based on its ability to reduce infectious virus titers for a longer duration compared to oseltamivir. It is currently under Phase 3 trials in the US. Another candidate is the sialidase fusion protein DAS181 that underwent Phase 2 human trials demonstrating good tolerability and viral load reduction. It achieved fast track and orphan drug designations from FDA in 2017. Pretomanid, originally developed as a tuberculosis drug, displayed broad-spectrum anti-viral properties in animal studies and is now in Phase 2 trials for influenza. Pretomanid targets bacterial enzyme systems not present in humans or viruses, hence is less prone to resistance. Jerkovic and colleagues conducted Phase 1 studies on milipidine, a novel cap-dependent endonuclease inhibitor in healthy adult volunteers in 2019. The triple combination of oseltamivir, baloxavir, and umifenovir entered Phase 3 trials in China in 2019 to evaluate its efficacy compared to oseltamivir monotherapy for hospitalized patients. Continued evaluation of these candidates will help address current influenza therapeutic gaps.
New Combination Strategies
Taking clues from HIV antiretroviral regimens, combination antiviral strategies are now a major focus area to prevent resistance emergence. The rationale lies in simultaneously targeting distinct stages of the influenza virus life cycle using agents from different mechanistic classes, like entry inhibitors combined with replication blocking drugs. Preclinical testing of combinations comprising of zanamivir, laninamivir or peramivir along with amantadine or rimantadine have demonstrated additive to synergistic activity against different influenza A strains including adamantane-resistant variants. Various two and three-drug combinations of baloxavir, favipiravir, and oseltamivir have exhibited strong synergistic activity in influenza infected ferrets and human lung cell cultures. Clinical trials are planned to evaluate whether such combinations can improve treatment outcomes while deterring resistance. Host-targeted agents like recombinant RIG-I enhancers are also being explored for combination use to mimic innate immune responses lost through resistance mechanisms. Overall, employing combination regimens may help address many present limitations.
Despite global efforts over decades, influenza remains a serious public health threat with periodic pandemics and constant evolution of viral resistance. The lack of robust, safe, and long lasting immunity generated by influenza vaccines necessitates continued emphasis on developing effective therapeutics. While approved options exist, limitations like a narrow window for treatment initiation and emerging resistance still remain substantial challenges. Novel investigational antivirals targeting host factors, RNA elements and multi-stage viral processes hold promise to achieve pan-influenza activity and circumvent resistance mechanisms. Employing combination regimens from inception will likely be essential to maintain efficacy over time. Vaccines that induce robust and durable T cell immunity in addition to antibodies may also curtail epidemic and pandemic spread. Continued basic research uncovering influenza pathogenesis combined with accelerated clinical evaluation of the most promising candidates is key to eventually realizing durable influenza therapies capable of mitigating seasonal epidemics and future pandemics.
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About Author-
Alice Mutum is a seasoned senior content editor at Coherent Market Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital marketing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice's dedication to excellence and her strategic approach to content make her an invaluable asset in the world of market insights.
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