Fast-acting flu drug shows strong potential, but clinical trial results also raise concerns

A new, fast-acting flu drug showed strong potential but also some surprising and even concerning results in two newly published clinical trials.

The drug, baloxavir marboxil, cut the time people were sick with flu symptoms by a little over a day. And it dramatically reduced the amount of viruses that people with infections had in their upper respiratory tracts, suggesting they might be less likely to infect others through coughs and sneezes.

Still, the single-dose drug didn’t make people feel better faster than oseltamivir, sold as Tamiflu.

And the studies, published last week in the New England Journal of Medicine, showed viral resistance could develop rapidly to the drug — a finding flagged as concerning in an editorial the journal published with the studies. Virus samples collected from nearly 10 percent of people treated in one of the trials showed mutations that are believed to allow the viruses to evade the effect of the drug.

There remains much hope attached to baloxavir, which is currently being given a priority review by the Food and Drug Administration. The FDA promised in late June to rule within six months — which means a decision should be made before Christmas.

“It looks like a very exciting drug. It’s a new [drug] class. Looks like it’s very efficacious. And it’s interesting because it has implications for patient care as well as for pandemic planning,” said Dr. Trish Perl, chief of infectious diseases at UT Southwestern Medical Center in Dallas. Perl was not involved in the research.

The drug was developed in Japan by Shionogi & Co. and sells there under the brand name Xofluza. Roche, the maker of the other main flu drug, Tamiflu, bought most of the global rights to baloxavir, and Roche’s subsidiary, Genentech, is developing it for the U.S. market. Shionogi retained the drug’s rights in Japan and Taiwan.

Genentech has not revealed what it intends to charge for the drug, which is taken in one or two pills, depending on body weight. In Japan, the drug sells for about $43.50, but that is for the one-pill dose. Hayden said the two-pill dose might be more common for North Americans.

Baloxavir is the first drug in a new class called endonuclease inhibitors. They work by interrupting viral replication — the process by which invading viruses take over the inner workings of cells to make zillions of copies of themselves to further spread the infection.

As Perl noted, a new influenza drug class is a cause for celebration for doctors who treat severely ill flu patients, and for public health officials responsible for planning for flu pandemics. There are currently only two classes of flu drugs on the market, though the drugs of one — the adamantine drugs — haven’t been recommended for use for years because most flu viruses have developed resistance to them.

The lead author of the studies, Dr. Frederick Hayden of the University of Virginia School of Medicine, is an expert on influenza antivirals. He has served as a consultant for Shionogi on the development of this drug, though his fees were paid to a charity.

“I’ve worked on flu antivirals since I started my fellowship in 1976. This is the most potent single agent that I’ve seen to date in terms of its effect on replication in acute influenza,” Hayden told STAT.

Given how effective the drug is at interfering with replication, the fact that people in the trial who received it didn’t feel better faster than others who were given oseltamivir was a bit of a surprise, he admitted. But Hayden suggested this may indicate that many of the symptoms we experience during a bout of the flu — fever, aches, malaise — may be caused by the weapons the immune system unleashes to fight the infection.

The drug acts quickly, but must be taken quickly as well for maximum effect. The studies — a Phase 2 and a Phase 3, published together — found that people who took the drug within 24 hours of the start of symptoms felt better, on average, 33 hours sooner than people whose flu was untreated. But for those who started the drug later, their recovery was sped up by only about 13 hours.

That means there will likely be real-world hurdles to using the drug. Patients will have to see a doctor, get a prescription, and get it filled within hours of starting to feel sick to gain the benefits. Treatment with oseltamivir and other drugs in its class — neuraminidase inhibitors — needs to be started within 48 hours of symptom onset. (Oseltamivir treatment involves taking two pills a day for five days.)

Implementing “early treatment with baloxavir or neuraminidase inhibitors will remain challenging for clinicians and patients with influenza worldwide,” Dr. Tim Uyeki, an influenza expert at the Centers for Disease Control and Prevention, wrote in the editorial published by the journal.

Uyeki’s editorial raised concerns about the percentage of treated patients whose flu viruses developed mutations. Sometimes mutations that convey drug resistance undermine a virus’s ability to spread from person to person; it’s not currently known if that is the case with these mutations. But Uyeki said flu laboratories will need to be watchful to see if, once the drug is in use, resistance to the drug amplifies.

Hayden’s hope is that the drug will be useful in the treatment of severe influenza cases when given in combination with existing flu drugs or other new drugs making their way through the development pipeline.

In some cases, giving drugs in combination slows the development of resistance, but Perl noted that hasn’t yet been shown to be the case with the new drug. And studies investigating whether the drug is effective when given to people hospitalized with severe influenza — most of whom would be days into their illness — still need to be conducted.