“Why it took 20 years for new flu drug Xofluza to be out”

Interviewing Principal Global Medical Director Aeron Hurt at Roche

“The antiviral treatment provides convenient administration as a one-dose oral medicine”

“Treating with credible antiviral from the initial phase of treatment is most important”

Since the 2009 flu pandemic, Tamiflu became a prescription drug with household name like Viagra.

 

Tamiflu (oseltamivir) is a good drug.

 

It shifted the world’s paradigm on influenza management and became the symbol of neuraminidase inhibitor drug.

 

However, the unmet medical needs still exist in the market.

 

Antiviral agent can always develop resistance, but for influenza treatment, no other agent than neuraminidase inhibitor is recommended.

 

In Korea, the influenza vaccination rate boasts a top world class level, but 2.26 million patients have been infected with influenza in 2018.

 

After two decades since Tamiflu was commercialized, Roche has showcased Xofluza (baloxavir).

 

The new drug has a novel mechanism of action that inhibits polymerase acidic endonuclease and treats influenza with only a single dose (Tamiflu requires a five-day treatment).

 

Daily Pharm met with Roche’s Principal Global Medical Director, Aeron Hurt, and spoke with him about the meaning and possibility created by developing Xofluza.

 

He used to serve as a senior research scientist at the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza.

 

-What was your role at WHO?

 

And what motivated you to be interested in influenza out of all infectious disease to study?

 

At WHO, I led a team of researchers to analyze and monitor antiviral agents and vaccine for patients with influenza.

 

Analyzing antiviral agents and vaccines’ effect at a research center in Melbourne, Australia, I came to realize the necessity and urgency to mange influenza better and more effectively.

 

And naturally, I got interested in and passionate about advocating the importance of antiviral agent and vaccine to effectively manage influenza.

 

-When it comes down to ‘influenza management,’ it is divided into ‘prevention’ and ‘treatment’ blocking the viral transmission.

 

What is your idealistic management plan incorporating the two factors?

 

First, the National Immunization Program (NIP) has to generate the maximum effect with limited resource.

 

Accordingly, the government could consider conducting or expanding NIP focusing on patient group with high risk of inducing complications or with possibility of optimal vaccination effect.

 

As WHO recommends, patient groups of the highest priority for vaccination—the elderly, children, individuals at high risk of medical complications and pregnant women—should be provided with quadriavalent vaccine than trivalent vaccine for better coverage of influenza vaccination.

 

As far as treatment goes, it is crucial to use an exceptional antiviral treatment as promptly and widely as possible when it is released.

 

Same goes for Xofluza and other antiviral treatment to be released in the future.

 

Instead of saving the new and effective antiviral treatment as a last resort for a pandemic, patients’ symptoms should be alleviated by treating the patient with effective antiviral from the beginning, while social and financial burden of influenza should be lowered.

 

-It sounds like you have Xofluza in mind.

 

Could you elaborate on the major clinical outcomes of the treatment for the readers to fathom its efficacy?

 

Xofluza demonstrated its positive efficacy in CAPSTONE-1 study treating a healthy patient group aged 12 to 64 diagnosed with acute influenza symptoms and CAPSTONE-2 study treating patient group aged over 12 at high risk of serious flu complications.

 

Top-line findings of CAPTSONE-1 study evaluating the flu treatment on healthy adult and adolescent, Xofluza reduced the median time to alleviation of symptoms by approximately 26.5 hours compared to the placebo group.

 

And it also demonstrated comparatively faster cessation of infectious viral shedding than the placebo.

 

Xofluza’s median time of viral shedding marking 24.0 hours (about a day) was meaningful, as the placebo group took 96.0 hours (about four days) and oseltamivir group took 72.0 hours (about three days).

 

Meanwhile, the CAPSTONE-2 study evaluated the treatment’s effect on elderly patient and who are at a high risk for influenza-related complications.

 

The study also found exceptional effect of Xofluza as its median time to alleviation of symptoms in high-risk patient group took 73.2 hours (about three days), cutting down around 29 hours from the placebo group (102.3 hours).

 

Moreover, Xofluza reduced the time to cessation of viral shedding in 48.0 hours, which was about more than 50 percent improvement than the placebo (96.0 hours) and oseltamivir groups (96.0 hours).

 

-In the CAPSTONE-1 study, pediatric patients aged 12 to 19 years did not receive Tamiflu.

 

What was the reason?

 

The study was conducted in the U.S.

 

and Japan from December 2016 to March 2017.

 

The reason why adolescent patients from 12 to 19 were not in the Tamiflu group was because Tamiflu was not recommended to adolescent patients in Japan when the study initiated.

 

Currently, the limitation has been lifted.

 

For your reference, CAPSTONE-1 study had to apply equivalent condition to all participants in the U.S.

 

and Japan, so the U.S.

 

participants from age 12 to 19 only received Xofluza and placebo.

 

-The outcomes of CAPSTONE-1 does not seem to show significant difference between Xofluza and placebo arms’ time to alleviation of symptoms The time to alleviation of symptoms between two groups may not have shown exceptional difference as the evaluation of ‘symptom’ could be subjective.

 

The severity of symptoms could differ from each individual.

 

And a patient infected with influenza virus show cytokine response, which is induced regardless of decreased virus titer.

 

Therefore, it would be quite difficult to reduce the time to alleviation of symptoms by 24 hours more than the available antiviral agents, despite the new antiviral agent considerably shortens time of viral shedding.

 

The most important differences between Xofluza and existing antiviral treatment are reduced time of viral shedding and lessened risk of complications.

 

-With Tamiflu, there was an issue with neuropsychiatric events.

 

Was there any similar event reported from Xofluxa study?

 

The company is closely monitoring patients who have taken Xofluza, and there has not been any report of adverse neuropsychiatric event so far.

 

Influenza itself could affect patients in neuropsychiatric event.

 

And also, the correlation between oseltamivir and neuropsychiatric event in treated patient has not been proven.

 

So medical professionals should carefully consider treatment benefit and adverse reaction from antiviral treatment and prescribe Xofluza according to the patients’ individual conditions.

 

The same applies to Tamiflu.

 

Although there were reports of adverse reaction in Japan about a decade ago, but the Tamiflu prescription limitation has been lifted and the public’s perception has been changing as well.

 

-The present indication for Xofluza is quite narrower than other available flu treatments.

 

Are there any other ongoing clinical studies?

 

A few studies have been completed, but the outcomes have not been officially announced, yet.

 

They specifically were on post-exposure prophylaxis and pediatric patients.

 

The prophylaxis study evaluated probability of a patient diagnosed with influenza transmitting the virus to their household members, who have been administered with Xofluza.

 

The study result found the risk of influenza virus infection has gone down by 86 percent when administered with Xofluza.

 

Another clinical study, MINISTONE evaluated virus titer and time to alleviation of symptoms in children aged one to less than 12.

 

Also, there are three more clinical studies currently calling for participants.

 

The first one is for infants younger than 12 months, whereas the second one named FLAGSTONE is evaluating the efficacy and safety of Xofluza in combination with the current standard of care, compared to the standard of care alone from hospitalised patients.

 

The study would administer Xofluza not by single dose, but by total three times respectively on the first, fourth and seventh day of treatment.

 

Lastly, the CENTERSTONE study is reviewing Xofluza’s effect on patient’s viral infectiousness.

 

Unlike the previously mentioned post-exposure prophylaxis study, the treatment is administered not on the household members, but only on the patient.

 

The study aims to not only confirm time to alleviation of symptoms, but also the infectiousness to household members.

 

-Is there any other investigational drug in development at the moment?

 

Xofluza blocks polymerase acidic endonuclease, an enzyme crucial for viral replication.

 

Other candidate medicines inhibiting different enzymes are in R&D phase by other respective companies.

 

If these investigational medicines have successful clinical trials, they would be commercialized as well.

 

However, pharmaceutical companies, including Roche, have tried researching other mechanism of antivirus treatment like monoclonal antibody, but most of them have failed in clinical trial phase.

 

Considering the challenges, release of Xofluza is particularly meaningful.

 

The fact that Xofluza works in a novel mechanism of action, developed after twenty years, illustrates how the journey of developing an antiviral treatment is challenging and rough.