乌鸦传媒

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SAN FRANCISCO -- The single-dose antiviral medication baloxavir marboxil led to a decrease in the median duration of flu symptoms in two phase III trials, researchers reported here.

In a study of high-risk flu patients, those who received one oral dose of baloxavir experienced symptom improvement more than a day sooner than those assigned to placebo, and they were less likely to develop complications, said Michael Ison, MD, of Northwestern University Feinberg School of Medicine in Chicago.

Overall, baloxavir worked about as well as the widely used antiviral oseltamivir (Tamiflu), which is usually taken for 5 days. However, baloxavir was shown to be superior in people with type B influenza. In addition, people treated with baloxavir stopped shedding the virus sooner, which reduces opportunities for transmission.

"Time to cessation of viral shedding was more rapid in patients treated with baloxavir compared to placebo," Ison said.

In a late-breaking session, Ison from the CAPSTONE-2 trial. This study enrolled adolescent and adult patients (≥age 12) with symptomatic influenza who were considered to be at high risk for complications due to factors such as older age, compromised immune function, co-existing medical conditions, or residence in long-term care facilities.

Keiko Kawaguchi, MS, of Shionogi from CAPSTONE-1, which evaluated baloxavir in otherwise healthy individuals. The main results from this study, along with those from a prior phase II trial, were recently published in the New England Journal of Medicine.

Both studies were presented at the annual IDWeek meeting, jointly sponsored by the (IDSA), the (HIVMA), the (SHEA), and the (PIDS).

Baloxavir inhibits the influenza virus cap-dependent endonuclease protein, which is necessary for viral replication. It is designed to target influenza type A and B, including strains resistant to oseltamivir and avian strains. If approved, baloxavir would be the first flu medication with a novel mechanism of action to be developed in nearly 20 years, according to a , which is developing the drug in collaboration with Shionogi.

CAPSTONE-1 included 1,064 non-hospitalized patients in the U.S. and Japan during the 2016-2017 flu season. They had a confirmed diagnosis of uncomplicated influenza infection -- 87% with influenza type A(H3N2) and 8.5% with influenza B -- with an onset of symptoms within the past 48 hours. The median age was approximately 33 and about 25% were current smokers.

Adolescents (age 12-19) were randomly assigned to receive baloxavir or placebo, while adults age 20-64 had a three-way randomization to baloxavir, oseltamivir, or placebo. Baloxavir was given as a single oral dose of 40 mg or 80 mg, depending on weight, while oseltamivir was administered twice daily for 5 days.

As previously reported, the median time to alleviation of symptoms was 53.7 hours for people taking baloxavir, 53.8 for those taking oseltamivir, and 80.2 hours for those taking placebo. Baloxavir led to a greater reduction in viral load than either oseltamivir or placebo 1 day after treatment initiation. The frequency of adverse events was similar in the three arms (20.7%, 24.8%, and 24.6%, respectively).

Kawaguchi presented further data showing that the time to alleviation of symptoms was longer for patients in the U.S. (26% of the study population) compared with those in Japan. However, the reduction in time to improvement with baloxavir relative to placebo was similar in both countries (87.3 vs 117.9 hours in the U.S; 46.4 vs 77.7 hours in Japan). The time to symptom relief was longer for people who had more symptoms at study entry, those with influenza B, and non-smokers, Kawaguchi reported.

Although baloxavir reduced virus levels relative to placebo across the board, the benefit was greatest for people who started treatment sooner. The time to symptom relief was 49.3 hours with baloxavir versus 82.1 hours with placebo for those treated within 24 hours of symptom onset, increasing to 66.2 versus 79.4 hours, respectively, for those who started 24 to 48 hours after symptoms appeared. Early treatment led to faster alleviation of symptoms, Kawaguchi said.

High-Risk Patients

These findings set the stage for CAPSTONE-2, which included more people with characteristics linked to longer symptom duration and developing flu-related complications.

This trial included 1,163 non-hospitalized patients with a confirmed diagnosis of symptomatic, uncomplicated influenza within 48 hours of symptom onset. They were randomly assigned to receive baloxavir (40 or 80 mg), oseltamivir (75 mg twice daily), or placebo.

In this study, just over half were in North America or Europe and about 40% were in Asia. The age was considerably older -- approximately 52 years -- and about 15% were smokers. The most common risk factors were asthma or other chronic lung disease (39%) and age >65 (27%). Influenza A(H3N2) accounted for 48% of cases, followed by influenza B (42%) and A(H1N1) (7%). About one in 10 patients started treatment within 12 hours of symptom onset, about a third each did so within 24 hours and within 36 hours, and the rest did so within 48 hours.

Symptoms improved in a median of 73.2 hours with baloxavir, 81.0 hours with oseltamivir, and 102.3 hours with placebo. That is, baloxavir brought relief 29.1 hours sooner than placebo, Ison said. Baloxavir performed significantly better than placebo (P<0.0001), but was statistically similar to oseltamivir .

However, when looking only at patients with harder-to-treat type B influenza, the median time to improvement was 74.6 hours with baloxavir, 101.6 hours with oseltamivir, and 100.6 hours with placebo, indicating that baloxavir was statistically superior to both comparators (P<0.05).

Baloxavir was associated with a greater decrease in virus titer than either oseltamivir or placebo (P<0.05). The difference was especially pronounced for influenza type B, where baloxavir led to a nearly 3 log₁₀ drop in virus levels, while oseltamivir and placebo both produced about a 1 log₁₀ drop. Baloxavir recipients stopped shedding virus sooner (median 48.0 hours) than those taking either oseltamivir or placebo (median 96.0 hours for both; P<0.0001).

While not involved with the research, Angela Branche, MD, of the University of Rochester Medical Center in New York, said that the most important finding was the significantly decreased time to viral clearance with this treatment, but added that more research may be needed into resistance variants and mutations associated with the use of influenza-specific antiviral agents.

“Further study is needed to determine the frequency of reduced susceptibility to baloxavir,” she told 乌鸦传媒, adding that resistance mutations were already detected in a small portion of patients in both the phase II and III trials. “However, it offers a promising alternative to treatment with oseltamivir, especially for patients infected with a virus that has developed resistance to this agent.”

Examining complications, both baloxavir and oseltamivir were associated with a lower incidence of sinusitis (0.3% and 0.5% versus 2.1%, respectively) and bronchitis (1.8% and 2.3% versus 6.0%) compared with placebo, and fewer patients needed systemic antibiotics for secondary infections (3.4% and 3.9% versus 7.5%).

Treatment was safe and generally well tolerated, Ison reported. Serious adverse events (0.7%-1.2%) and drug discontinuation due to adverse events (0.6%-0.7%) were rare in all three treatment arms. Just 5.6% of baloxavir recipients experienced treatment-related adverse events.

"Oral baloxavir marboxil is a promising treatment option for patients with risk factors for influenza complications," the researchers concluded.

Session moderator Timothy Uyeki, MD, MPH, of the CDC, recently commented on the potential of baloxavir in an .

Reduction in viral replication with baloxavir has the potential to reduce the spread of influenza virus -- for example, within households or during outbreaks in long-term care facilities, Uyeki said. He also suggested that combination treatment with baloxavir and oseltamivir should be studied for very high-risk patients.

"If a single dose is successful in reducing influenza virus transmission, baloxavir could be a useful tool for seasonal and pandemic influenza preparedness and response," Uyeki wrote.

Baloxavir was granted FDA priority review status in June and an approval decision is expected in late December, according to Genentech. In February 2018, the drug was approved in Japan, where it is sold under the brand name Xofluza. Genentech announced that it will evaluate baloxavir in severely ill hospitalized influenza patients in partnership with the U.S. Biomedical Advanced Research and Development Authority.