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Oseltamivir (Tamiflu)

The neuraminidase inhibitor oseltamivir was developed by Gilead. It was licensed to Roche and is marketed under the brand name Tamiflu.
Due to the popularity of the Tamiflu brand, it was associated with the broader issue of non-disclosure of pharmaceutical data, which still is an issue, but has improved.
While disregard for a critical drug review process is mostly associated with Relenza, the review of Tamiflu happened at roughly the same time in the same regulatory environment.
Despite all the criticism and the rather low efficacy associated with Tamiflu, it was commercially wildly successful. With GSK not doing much to further sales of Relenza, influenza becoming widely resistant to Amantadine and Rimantadine just a few years after Tamiflu market entry, and repeated concerns about (avian) influenza, enormous amounts of Tamiflu were stockpiled and more than 200 million patients have been treated.
While the oseltamivir patents have expired around 2016, Xofluxa, the next influenza drug marketed by Roche, has been approved in 2018.

In fact, the methods and results of clinical trials on the drugs we use today are still routinely and legally being withheld from doctors, researchers and patients. It is simple bad luck for Roche that Tamiflu became, arbitrarily, the poster child for the missing-data story.
Source: What the Tamiflu saga tells us about drug trials and big pharma
Though Tamiflu became, in a way, the poster child for the problem of non-disclosure, there are probably many other drugs out there with doctors making treatment decisions based on incomplete and misleading data.
Source: Medical Data Transparency and the Tamiflu Controversy
Tamiflu, used to treat influenza, really had only modest benefits. However—and this part of the review was largely ignored by the media—Tamiflu was successful in preventing influenza: 55 percent overall and 80 percent effective if looking only at household members exposed to flu.
Source: Medical Data Transparency and the Tamiflu Controversy
The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and Roche (the originator) reject the conclusions of the Cochrane Review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza.
Source: Oseltamivir
We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (...). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups(...).
Source: Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials
In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy and was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else.
Source: Zanamivir
The new guidelines would bring the stockpile to 195 million doses.
Source: U.S. to boost Tamiflu, Relenza stockpiles
More than 70 governments have placed orders for Tamiflu, and at least 220 million treatment courses have been stockpiled since 2003 at a cost of $6.9 billion. Roche is producing 110 million courses for the 5 months from May to fall 2009 and will produce up to 36 million courses per month by year’s end if necessary.
Source: Maximizing the Value of Drug Stockpiles for Pandemic Influenza
The government spent £424m stockpiling a drug to treat flu despite there being question marks over the effectiveness of the medicine called Tamiflu, a public spending watchdog has found.
Source: Tamiflu drug bill 'shocking waste of taxpayers' money'
Interim CDC guidanceopens in a new tab or window suggests initiating antiviral treatment with a neuraminidase inhibitor as early as possible for symptomatic outpatients, and using oseltamivir to treat severe, progressive, or complicated H5N1. For people who meet the epidemiologic exposure criteria, oseltamivir also is recommended as prophylaxisopens in a new tab or window. Still, Schaffner noted that "antivirals are by no means a panacea." Andrew Pavia, MD, professor and chief of the division of pediatric infectious diseases at the University of Utah in Salt Lake City, said that while evidence indicates oseltamivir would be effective, "effective doesn't mean it's an ideal drug." For instance, oseltamivir, like other antivirals, is most effective if taken in the first 48 hours, which can be a difficult window to catch.
Source: Do Our Flu Antivirals Work on H5N1?

Zanamivir (Relenza)

The neuraminidase inhibitor zanamivir was developed by Biota, now part of Vaxart, relying on research by CSIRO. It was licensed to GSK. Marketed under the brand name Relenza as an alternative to Tamiflu, the market share quickly fell from 50% to 3%, highlighting the risks of relying on a bigger partner for marketing. While Relenza and Tamiflu are similar, Relenza is a powder, not a pill like Tamiflu. While inhalation provides direct access to the lungs and fewer side effects were reported, inhalation can obviously be more difficult. This was a concern for GSK. Intravenous application of Relenza has been tested, with positive results.
Due to copyright limitations it is recommended to read this article, maybe this article, and certainly the whole interview with Michael Elashoff.
The patents have expired roughly ten years ago, so there are no more royalties for Biota to claim from GSK.

"Relenza was a breakthrough influenza drug that had great potential, but it was effectively abandoned at birth."
Source: Biota sues GSK for lost Relenza revenues
Biota, which licensed Relenza to GSK in 1990, had claimed GSK had breached its contract to adequately promote and market the drug, causing it to lose millions in royalties.
Source: Biota, GSK settle legal action
Biota is entitled to a 7% royalty (...) on all sales of Relenza by GSK through to the end of the product's patent life (2014 in the US; 2011-2013 in other countries).
Source: Sold Short: What happened to Relenza™
Since 2002, governments around the world have spent billions of dollars stockpiling neuraminidase inhibitors (NIs) such as Tamiflu® (oseltamivir) and Relenza® (zanamivir) in anticipation of an influenza pandemic. This trend increased dramatically following the outbreak of the H1N1 virus (swine flu) in April 2009.
Source: Tamiflu and Relenza: getting the full evidence picture
Despite meeting deliberations about pandemic risks and the pressing need for new anti-influenza drugs, there was an overriding concern about Relenza’s limited efficacy, especially in the US population, and the panelists therefore voted 13 to 4 against recommending approval (FDA, 1999d). The negative votes included some of the country’s top influenza experts, including the Chief of the Influenza Branch of the Centers for Disease Control (CDC).
Source: The will of Congress? Permissive regulation and the strategic use of labeling for the anti-influenza drug Relenza
Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.
Source: Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

Peramivir (Rapivab)

The neuraminidase inhibitor peramivir was developed by BioCryst Phamarceuticals. It is marketed under the brand name Rapivab by BioCryst Phamarceuticals.  This study reports a highly reduced susceptibility to peramivir in case of the NA-H275Y mutation, although 3 to 4 times less reduced than against oseltamivir. This study shows that the NA-S247N mutation causes resistance to oseltamivir and zanamivir, but causes no resistance against peramivir.

Peramivir is administered as a single-dose via the intravenous route providing a valuable therapeutic alternative for critically ill patients or those unable to tolerate other administration routes.
Source: Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections
Dec 22, 2014 Approval FDA Approves Rapivab (peramivir) to Treat Influenza Infection
Source: Rapivab FDA Approval History
In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation.
Source: Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation
Both peramivir groups were noninferior to the oseltamivir group (...). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.
Source: Phase III Randomized, Double-Blind Study Comparing Single-Dose Intravenous Peramivir with Oral Oseltamivir in Patients with Seasonal Influenza Virus Infection
Our results show that peramivir is generally safe and is expected to be consistently effective after a single intravenous administration at a dose of 300 or 600 mg, regardless of the viral subtype, including A/H1N1, A/H3N2, and B influenza viruses. In addition, treatment with peramivir can be completed with a single intravenous dose, thus ensuring good compliance. These results highlight the usefulness of single-dose intravenous peramivir as an effective therapy for patients with seasonal influenza virus infection.
Source: Phase III Randomized, Double-Blind Study Comparing Single-Dose Intravenous Peramivir with Oral Oseltamivir in Patients with Seasonal Influenza Virus Infection
The studies have shown that peramivir resistance among influenza A/H1N1pdm09 viruses ranges from 1.3%–3.2% and is less than 1% for influenza A/H3N2 and B viruses. The most commonly occurring mutation leading to reduced effectiveness of peramivir is H274Y (H275Y N1 numbering), resulting in a 100–400-fold increase in IC50. It appears rapidly in immunocompromised individuals or hematopoietic cell transplant recipients treated with peramivir administered via the intravenous route. In vivo studies on mice showed that peramivir could be effective in the treatment of infections caused by oseltamivir-resistant A/H1N1/H274Y influenza virus.
Source: Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
In vitro studies demonstrated that passaging of the A/H3N2 virus in the presence of peramivir led to the emergence of strains with reduced susceptibility to peramivir, which was related to the K189E mutation in the HA protein. The R294K mutation in the N9 neuraminidase resulting in high-level resistance to peramivir was detected in clinical strains.
Source: Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
Of the 22 S247N variants detected, nine were cultured and in an NA inhibition assay showed a mean six-fold reduction in oseltamivir sensitivity, a three-fold reduction in zanamivir sensitivity, and no significant reduction in peramivir sensitivity compared to the mean IC50 (concentration required to inhibit 50% of NA activity) of sensitive influenza A(H1N1)2009 viruses (Table).
Source: Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation

Baloxavir (Xofluxa)

Baloxvair is an endonuclease inhibitor developed by Shionogi. It is marketed by Roche under the brand name Xofluxa. The main advantage of this relatively new drug, approved in 2018, is that it is not another neuraminidase inhibitor. This different mechanism reduces the risk of resistance mutations. However, the PA/I38T/F/M/N/S mutation, causing resistance to Xofluxa, seems to appear quite often.
Since baloxavir is an endonuclease inhibitor and all other drugs actively used are neuramidase inhibitors, they target different enzymes of the virus. While this makes a combination therapy seem like a good idea, it doesn't work.

The FDA granted approval of Xofluza to Shionogi & Co., Ltd.
Source: Food and Drug Administration (FDA)
“Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.” (...)
In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.
Source: Food and Drug Administration (FDA)
Frequency of viruses showing reduced inhibition by NA inhibitors remained low (0.5–0.6%) during 2018–2020. Frequency of viruses showing reduced baloxavir susceptibility was low (0.1–0.5%) but elevated (4.5%) in Japan in 2018–2019.
Source: Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018–2020
Viruses bearing the PA/I38T/F/M/N/S mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir with changes in EC50 values ranging from 11 to 57-fold for influenza A viruses and 2 to 8-fold for influenza B viruses.
Source: SUMMARY OF PRODUCT CHARACTERISTICS
In fact, baloxavir represented 40 percent of the market share of influenza drugs in Japan during the 2018-2019 flu season. susceptibility to baloxavir with changes in EC50 values ranging from 11 to 57-fold for influenza A viruses and 2 to 8-fold for influenza B viruses.
Source: New flu drug drives drug resistance in influenza viruses
In fact, a previous study in pediatric patients showed the mutation appeared in the samples collected from nearly 1 in 4 of the 77 children enrolled who were also treated with baloxavir. susceptibility to baloxavir with changes in EC50 values ranging from 11 to 57-fold for influenza A viruses and 2 to 8-fold for influenza B viruses.
Source: New flu drug drives drug resistance in influenza viruses
Combining baloxavir with NAIs did not result in superior clinical outcomes compared with NAIs alone.
The combination of baloxavir plus NAI was well tolerated. The findings suggest that combination antivirals would not be routinely indicated in clinical practice for hospitalised patients with severe influenza.
Source: Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial
When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. (...) For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness.
Source: Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus
Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival.
Source: Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection

Laninamivir (Inavir)

Laninamivir is a neuraminidase inhibitor developed by Daiichi Sankyo. It is marketed by Daiichi Sankyo under the brand name Inavir. Just like Relenza, Inavir is a powder to be inhaled.

Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo), announced today that it received approval in Japan to market Inavir® Dry Powder Inhaler 20mg (generic name: Laninamivir Octanoate Hydrate) for the prevention of influenza in both adults and children.
Source: Daiichi Sankyo Receives Approval for the Use of Inavir® to Prevent Influenza
The concentration of the drug in the respiratory tract exceeds the IC50 for influenza virus even up to 240 hours after inhalation.
Source: Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
Laninamivir is an effective treatment for highly pathogenic avian influenza A/H5N1 and A/H1N1pdm09 viruses, as well as strains resistant to oseltamivir and zanamivir. In vitro studies showed that the drug remains in high concentration in the lungs for a long time. It binds to the viral neuraminidase more stably in comparison to other neuraminidase inhibitors. Its antiviral activity is achieved with a single dose (40 mg, via inhalation).
Source: Evolution of Influenza Viruses—Drug Resistance, Treatment Options, and Prospects
Laninamivir was the most widely used antiviral for the treatment of influenza in Japan before the launch of baloxavir. According to reports of the Japanese Ministry of Health, Labor and Welfare, laninamivir's market share was about 47% in the 2015–2017 influenza seasons. After the launch of baloxavir, in 2018–2019 lanamivir had the second largest market (21%) after baloxavir (38%).
Source: Cost-effectiveness of baloxavir marboxil compared to laninamivir for the treatment of influenza in Japan

Favipiravir (Avigan)

Favipiravir is a polymerase inhibitor developed by Toyama Chemical, a subsidiary of Fujifilm. It is marketed by Fujifilm under the brand name Avigan. Avigan is very effective against H5N1 in mice, doesn't seem to create resistances, and targets and broad spectrum of RNA viruses, for example Ebola. The effectiveness against SARS-CoV-2 seems to depend on beginning the treatment early.
Unfortunately Avigan has the potential to harm embryos, it is teratogenic and embryotoxic in animals. The use of Avigan is therefore severely restricted.

This drug functions as a chain terminator at the site of incorporation of the viral RNA and reduces the viral load. Favipiravir cures all mice in a lethal influenza infection model, while oseltamivir fails to cure the animals. Thus, favipiravir contributes to curing animals with lethal infection. In addition to influenza, favipiravir has a broad spectrum of anti-RNA virus activities in vitro and efficacies in animal models with lethal RNA viruses and has been used for treatment of human infection with life-threatening Ebola virus, Lassa virus, rabies, and severe fever with thrombocytopenia syndrome. The best feature of favipiravir as an antiviral agent is the apparent lack of generation of favipiravir-resistant viruses. Favipiravir alone maintains its therapeutic efficacy from the first to the last patient in an influenza pandemic or an epidemic lethal RNA virus infection. Favipiravir is expected to be an important therapeutic agent for severe influenza, the next pandemic influenza strain, and other severe RNA virus infections for which standard treatments are not available.
Source: Favipiravir, an anti-influenza drug against life-threatening RNA virus infections
Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies.
Source: Favipiravir (T-705), a novel viral RNA polymerase inhibitor
When favipiravir was orally administered 2 or 4 times a day for 5 days in mice infected with lethal doses of influenza virus A/Victoria/3/75(H3N2), A/Osaka/5/70(H3N2) or A/Duck/MN/1525/81(H5N1), improved survival compared to placebo was shown at a dose of 30 mg/kg/day or more. The drug also provided significant protection against the A/Duck/MN/1525/81(H5N1) virus at a dose of 33 mg/kg/day or more, regardless of the number of daily doses. When given 4 times a day, all mice survived. In contrast, oseltamivir therapy failed to impact survival at a dose of 20 mg/kg twice daily for 5 days.
Source: Favipiravir (T-705), a novel viral RNA polymerase inhibitor
Under this agreement, Fujifilm grants Hisun Pharmaceutical a license to use its Favipiravir-related patents** in China to develop, manufacture and market an anti-influenza drug in China. Fujifilm will receive a lump-sum payment and royalties once such a influenza drug is successfully introduced to the market. Avigan Tablet, created by the Fujifilm Group company Toyama Chemical Co., Ltd., is an anti-influenza drug approved for manufacturing and marketing in Japan in March 2014.
Source: Fujifilm Signs A Patent License Agreement On Its Anti-Influenza Drug Avigan Tablet* With China's Major Pharmaceutical Company Zhejiang Hisun Pharmaceutical
Clinical trials of treatments for seasonal influenza have been performed in Japan and the US, and favipiravir was approved as a treatment for novel or re-emerging influenza viruses in Japan in 2014. However, favipiravir (Avigan®) is only considered for administration to patients when the government judges that this drug will be used as a countermeasure for novel or re-emerging influenza viruses. In addition, favipiravir is contraindicated for use in pregnant women because it exerts teratogenic and embryotoxic effects on animals.
Source: Favipiravir, an anti-influenza drug against life-threatening RNA virus infections
Avigan® is an anti-influenza drug that had obtained manufacturing and marketing approval in Japan in March 2014 with an indication to treat new or reemerging influenza viruses. Administration of the drug to patients is considered if the government deems it necessary following the outbreak of a new or re-emerging influenza virus infection, to which other anti-influenza drugs prove ineffective or produce only insufficient effects.
Source: FUJIFILM Toyama Chemical discontinues development of “Avigan® Tablet” anti-influenza drug as a treatment for COVID-19
This is probably a reference to Avigan tablets in Japan, which have been approved but are not currently on the market, but there are problems such as teratogenicity, so we have to be very careful when using these tablets. However, in an emergency situation such as the one we are facing now, we do not consider it a violation of the Pharmaceutical Affairs Act per se to use the drug at the discretion of the doctor, or to use it by prescription.
Source: 田村大臣閣議後記者会見概要
Doctors in Japan are using the same drug in clinical studies on coronavirus patients with mild to moderate symptoms, hoping it will prevent the virus from multiplying in patients. But a Japanese health ministry source suggested the drug was not as effective in people with more severe symptoms. “We’ve given Avigan to 70 to 80 people, but it doesn’t seem to work that well when the virus has already multiplied,” the source told the Mainichi Shimbun.
Source: Japanese flu drug 'clearly effective' in treating coronavirus, says China