3. S1 Episode 3: A review of Baloxavir®, an antiviral treatment for influenza A and B.

Dr. Rupeena Purewal, pediatric infectious disease physician, reviews Balxoavir Marboxil®, an oral antiviral medication for treatment of influenza A and influenza B flu. Baloxavir® was approved for medical use in Canada in 2020.

Canadian Baloxavir Product Monograph : [Product Monograph Template - Standard] (hres.ca)

Episode Transcript

(00:00):
Hi and welcome to another episode of the Canadian Breakpoint, a Canadian infectious disease

(00:12):
podcast by infectious disease physicians.
I'm Summer Stewart, here with Dr. Rupeena Purewa, pediatric infectious disease specialist
from Saskatoon.
For this episode, Dr. Purewal will discuss Biloxavir in anticipation of the 2021 flu
season.
Hi everyone, welcome to another episode of our podcast, the Canadian Breakpoint.

(00:35):
Today we'll be discussing Biloxavir, which is an antiviral that was recently approved
by Health Canada in February 2020 for acute uncomplicated influenza infections in those
12 years of age and older.
I wanted to review this topic for multiple reasons, one being that our last influenza
season was very different here in Canada and probably globally due to many factors, likely

(01:00):
an increase in flu vaccine uptake versus universal masking that's been in effect.
Now as many of us are aware, this winter season, our respiratory season, may look more similar
to our normal respiratory season with some increased influenza cases and therefore I
thought it was very timely for us to discuss a new antiviral that was on the market, Biloxavir.

(01:26):
And therefore, that's what we'll be talking about today.
Before I do start talking a little bit more about Biloxavir itself, I do want to mention
this is an informational podcast.
I do not have any financial disclosures and I'm not endorsing this product.
So today our objective will be to learn about Biloxavir, also known as Zofluza.

(01:52):
We will talk about the properties of Biloxavir, the indications, contraindications, and then
in the end we will compare it to our conventional antiviral, also known as Tamavir or Tamiflu.
So starting off with Biloxavir, Biloxavir marboxyl is the active ingredient, so the
product name is Zofluza, and the route of administration is oral.

(02:17):
When we will be prescribing or using this as a prescription medication, it comes in
a 20 milligram and a 40 milligram tablet.
So in terms of dosing for us clinicians, if your patient is between 40 to 80 kilos, then
two 20 milligram tablets for a total dose of 40 milligrams.
If they're greater than 80 kilos, then we're looking at two 40 milligram tablets for a

(02:41):
total dose of 80 milligrams.
Fortunately it's a single dose regimen that's given within 48 hours of symptom onset.
Now going on to the indications, as were listed in the product's monograph, it's indicated
for the treatment of uncomplicated influenza, as we mentioned, in patients that are 12 years

(03:01):
of age and older, who have been symptomatic for no more than 48 hours and who are otherwise
healthy or at high risk of developing influenza complications.
There's no clinical evidence for efficacy outside of influenza A and B, so not recommended
for other viruses.
And again, there's no efficacy or safety that's been established in those that begin therapy

(03:26):
or treatment after the 48 hour mark.
Also there's no efficacy or safety in treatment of influenza in patients requiring hospitalization,
so those you would encounter more of your complicated influenza cases.
And also kind of different from our also Tamifir antiviral medication, there's no efficacy

(03:47):
here with Biloxavir in preventing influenza.
Now going on to the mechanism of action, so Biloxavir merboxyl is a pro drug that's converted
by hydrolysis to its active metabolite, Biloxavir.
This active form exerts the anti-influenza activity.
So it actually acts on the cap-dependent endonuclease, which is an influenza virus specific enzyme

(04:13):
and actually the PA, or polymerized acidic subunit of the viral RNA polymerase complex.
So really the way it works is it inhibits the transcription of influenza virus genomes
resulting in inhibition of influenza virus replication.
Looking at the pharmacokinetics of this drug, Biloxavir, the terminal elimination half-life

(04:40):
of Biloxavir after your single oral administration dose is 79.1 hours and it's mainly excreted
via the fecal route in humans in small amounts in the urine.
So obviously as clinicians, I think it's really important for us to talk about efficacy and
also safety.
And so based on the monograph, they did discuss two clinical trials that we're going to talk

(05:03):
about right now, but really basing it on that there was significant reduction in the time
to alleviation or time to improvement of influenza symptoms with sofluza compared to the placebo
group.
So the two clinical trials, so the first trial was a phase three randomized double-blind

(05:24):
multicenter placebo, an active controlled study designed to evaluate the efficacy and
safety of Biloxavir compared with the placebo arm or also Tamavir in healthy adults or adolescents,
that was your 12 to 64 years of age, weighing 40 kilos, all that had acute uncomplicated

(05:47):
influenza, so really the eligibility for this trial was that they had to have an auxiliary
temperature of 38 degrees Celsius or above, one respiratory symptom that was moderate or
greater than severity and one stomach symptom like headache, fever, chills of moderate or
greater severity.

(06:09):
All patients in this study were treated within 48 hours of symptom onset as per the indications
and dosing was 40 or 80 milligrams of sofluza or conventional dosing for Tamiflu and then
there was the placebo arm.
So really the design of the study was to do self-assessment which would require to assess

(06:32):
their symptoms as none, mild, moderate or severe, twice daily in the first nine days
and then once daily up to day 14.
So the primary efficacy endpoint was time to alleviation of symptoms and that was defined
when all symptoms were assessed as none or mild for a duration of at least 21 and a half

(06:54):
hours.
So this specific study had an N of 1400 patients that were randomized, the intention to treat
infected population included over a thousand patients with PCR confirmed influenza.
I think it's quite interesting for me to look at the predominant strains in this study and

(07:15):
it was mostly influenza type A H3 subtype, that was around 80% and then coming in second
was influenza B type at around 10% and then with the smallest number was influenza A H1
and one.
It was also notably mentioned in this trial that 75% of the patients enrolled did not

(07:42):
receive their influenza vaccine.
Now when looking at the primary endpoint which was that time to alleviation of symptoms,
a statistically significant improvement was seen with the Zofluza group when compared
to the placebo arm but there was no statistical significance that was seen in any difference

(08:03):
in time to alleviation of symptoms when we compared the Zofluza group to the ulceratomavir
group.
As for the secondary endpoint which is time to resolution of fever was also noted that
was faster in the Zofluza group compared to the placebo arm with a median time with the
Zofluza group around 24 and a half hours compared to the patients that were in the placebo group

(08:27):
which was up to 42 hours.
Now as mentioned previously there was two trials that were discussing the efficacy and safety.
So the second trial was a phase three randomized double-blinded multi-center placebo and active
control study to evaluate efficacy and safety.
Again of the oral dose of Zofluza compared to the placebo arm or also tamivir in adolescents

(08:53):
and adult patients older than 12 years of age.
Now with influenza who are at high risk of developing influenza related complications.
So the patients that were included under the high risk or kind of what we see in our probably
clinical practice but most commonly was represented in this study was underlying asthma, chronic

(09:15):
lung disease at around 40%, diabetes at around 20% and then followed by heart disease and
obesity around the 12% range.
The patients that were excluded were if they had cancer in the last five years untreated
HIV or treated HIV with a low CD4 count of below 350 immune suppressed patients falling

(09:40):
transplant so really anybody really in your immunocompromised state.
Now most patients in this clinical trial also had not received their influenza vaccine.
Eligibility was very similar to the previous study and the number of patients that were
randomized were over 2100 and over 1100 of them had confirmed diagnosis of PCR at the

(10:05):
study entry.
The predominant strains here were influenza A H3 subtype very similarly but there was
more of a 50-50 distribution here with influenza B coming in second and when looking at the
primary endpoint here which is time to improvement of symptoms there was again statistical significance

(10:25):
for the Zofluza group compared to the placebo group but again no significant improvement
difference that was noted in the Zofluza group and comparing it to the ulceratoma beer group.
It's very similar to our previous trial that we just discussed.
In terms of the secondary endpoint which is resolution of fever, fever was reduced more
rapidly in the Zofluza group compared to the placebo group.

(10:49):
So I think all in all looking at both the healthy subjects in the first trial and the
high risk subjects in the second trial as we just discussed the Zofluza group for both
their primary and secondary endpoint did better than the placebo group I think is what mainly

(11:13):
I took from this study and it was also so as we mentioned in the second trial they were
looking at high risk patients who have a higher risk of developing or higher risk of developing
influenza related complications and so they specifically mentioned in the monograph the
overall incidence of influenza related complication was around three percent in the Zofluza group

(11:38):
compared to the placebo group which was up to ten percent.
So that was another important measure and really they looked at they had a lower incidence
in these patients in the Zofluza group lower incidence of bronchitis and sinusitis.
However there was no significant differences in some of our higher risk complications or

(12:01):
more complicated presentations such as death, hospitalization, and Titus pneumonia.
So I think that overall summed up the efficacy of Bloxivir.
In terms of as clinicians I think it's also really important to know the safety and so

(12:21):
looking at what the monograph stated safety was submitted and reviewed by Health Canada
and safety and efficacy had been established for children that are older than 12 years
of age and weighing greater than 40 kilos so it was not well established outside of
that age range and outside of that weight.

(12:42):
In terms of pregnancy and breastfeeding so definitely there are no well controlled studies
in this population which is usually the case in most of the drugs that get released on
our market however the current recommendations in your pregnant patients or those that are
breastfeeding there's no kind of well controlled studies as we mentioned so the current recommendation

(13:09):
is that currently should not be used during pregnancy unless there's really a potential
benefit that justifies the risk to the fetus.
When they did look at higher doses of Bloxivir in for instance like pregnant rabbits at six
times higher dose than what we would be giving to humans they did see that there was maternal

(13:29):
toxicity leading to miscarriages and increased incident in minor skeletal abnormalities but
this was not obviously seen in some of the other subjects that were used and then in
pregnancy we just don't have those studies right now.
In terms of any contraindications so avoiding it in those that ever have any hypersensitivity

(13:52):
to this drug or any ingredient in the formulation such as anaphylaxis, aorticaria, angiotema.
I think it was important for the part of the monogram that mentioned kind of dosing considerations
you want to avoid giving it with any calcium beverages so pretty much all in all avoid
dairy products anything that could combine with the medication that would make it more

(14:20):
or make it ineffective.
Antacids were on the list, oral supplements like calcium, iron, magnesium, selenium or
zinc as well and some laxatives that have polyvalent cations.
So definitely taking that into consideration especially for our pharmacy folks that are
helping us prescribe this medication.

(14:41):
They also mentioned in the monograph that it was not well studied in renal impairment
in patients and those with severe hepatic disease but currently there are no change
in dose recommendations so no dose changes required for both renal and hepatic impairment.
In terms of side effects so in the clinical trials themselves they saw some mild side

(15:05):
effects the GI upset which is a really common manifestation that was seen in those patients
including nausea and diarrhea but also developing other milder symptoms of bronchitis, sinus
infection or headache and when looking at it more so in the post marketing adverse events

(15:27):
anaphylaxis, angioedema, urticaria and rash were seen vomiting, bloody diarrhea, melanitis,
ischemic colitis however as we're aware these are reported voluntarily from a population
of an uncertain size so really can't reliably estimate their frequency so much that would
be what we can do in the clinical trials and it seems like in the clinical trials really
the milder symptoms were more predominant however with age nausea was also a predominant

(15:52):
finding so that's something to consider in your patients when prescribing it and obviously
with any other medications if there is any severe reaction should always counsel your
patients to stop taking the medication and speak to the health care provider.
So there was an interesting part of the monograph that was brought up in terms of resistance

(16:15):
or development of resistance and treatment emergent amino acid substitution resistance
that have something they've been noticing in the US so it since FDA approval in the
US which is back in 2018 they are seeing that now more so in vitro in clinical isolates
really it's the treatment emergent amino acid substitution and the PA protein which

(16:39):
showed mainly for influenza A virus isolates that there's a tenfold reduced susceptibility
but not so much or not as high in the influenza B group but still representing a fivefold
reduced susceptibility to block severe.
In the clinical trials and the healthy subjects this mutation at this amino acid substitution

(17:00):
position was seen in about 10% of the Zoflouza group and the high risk patients about 5%
of the patients that were seen had this mutation detected so just something to consider when
we are looking into prescribing so kind of the evidence or the supporting recommendations
that were given in regards to that was that health professionals should consider available

(17:21):
information on the influence of virus drug susceptibility patterns and treatment effects
when deciding whether to use Zoflouza if that's an option.
And so I'm kind of pretty much wanted to sum up this episode by comparing Tamiflu to Bloxivir
because I think most of us are quite aware of the properties of Tamiflu or also Tamivir

(17:48):
versus Bloxivir but really doing a side by side comparison can sometimes help especially
because these are the two antivirals that are on the market.
Most of us may not be familiar with Bloxivir because it was just released prior to the
COVID pandemic and since we didn't see much influenza activity in our last respiratory

(18:08):
season a lot of us probably did not prescribe this medication however we may be seeing a
different respiratory season coming forward in these winter months and so we'll just end
this podcast by talking a little bit about Tamiflu versus Bloxivir some of the properties
that stood out to me and will help me as well in my clinical practice.

(18:30):
So when we talk about cost I think it's always an important topic to bring up when we're
comparing medications and when we're prescribing medications so both of them are prescription
drugs Tamiflu is less costly whereas Bloxivir is more expensive so that's something to consider.
In terms of the mechanism of action Tamiflu as we're all aware stops the viral copies

(18:52):
from leading your cells to preventing you from becoming more sick whereas Bloxivir as
we just learned stops the influenza virus itself from actually making copies of itself
so the viral replication now both of them it's advised to take within 48 hours of feeling
sick and I think as a pediatrician it was actually quite important to me to know that

(19:13):
Bloxivir is only approved in those older than 12 years of age and greater than 40 kilos
whereas Tamiflu and what I see in my clinical practice as well as we can give it as young
as two weeks old and not only that but we can use Tamiflu or also Tamivir as a treatment
and prevention agent whereas Bloxivir as we just learned is only indicated for treatment

(19:39):
and just kind of remembering that Tamiflu can be given for your complicated patients
and is recommended whereas Bloxivir is more probably in your outpatient setting where you
have an acute uncomplicated influenza positive patient maybe somebody who is higher risk
for developing complications or even in our pediatric populations in that adolescent group

(20:01):
if you have a patient where you can detect them within the first 48 hours of feeling
sick and can give them a single dose probably helps with compliance that it's a single dose
as opposed to Tamiflu where you're taking it for five days twice a day dosing that's
probably the conventional dosing. Now I did want to kind of touch on the topic of antiviral

(20:22):
use in general because in the pediatric population we often kind of shy away from giving antivirals
especially Tamiflu which has been on the market for a long time and recently in the pediatric
journal there was a study that was released by Impact Network which is a pediatric hospital

(20:45):
national active surveillance network which is actually a really good paper that sums
up kind of the antiviral use in the pediatric population so it's only looking at from zero
to 16 years of age and was comparing our use in 2010 to 2011 compared to 2018 to 2019.

(21:05):
Now overall our use of antivirals despite the current recommendations from Canadian
Pediatric Society and the American Academy of Pediatrics stating that antiviral agents
are recommended for influenza especially in patients that are hospitalized patients even
if they've are past that 48 hour mark however overall use in our pediatric patients when

(21:30):
looking at the over 7500 cases we were only at around a use rate of about 41 percent so
definitely could be variable among centers different centers have different abilities
for testing and those that can test sooner obviously had higher rates so something to

(21:54):
consider so just coming into this respiratory season and likely our influenza season that's
something to consider and when they looked at the antiviral use rate in these pediatric
hospitals comparing it from the 2010 to the 2018-2019 data we did see that the overall

(22:15):
use had increased now whether that's again because of more testing or more complicated
patients for many reasons so it went from 20 up to 60 but I just wanted to kind of bring
that up because definitely there are benefits and a lot of observational studies that have
been seen in children and adults that are hospitalized that suggest clinical benefit

(22:39):
of antiviral use now whether that's decrease in length of stay decrease in health care
costs and decrease in our ICU and overall mortality morbidity so something to consider
for us as clinicians as well and and knowing of the indications for each of the antivirals

(23:00):
that are available to us on the market I think was one of the first steps for me just knowing
and learning about blocks of year because it was something that I definitely have not
encountered in my clinical practice just kind of remembering that now obviously we detoured
a little bit more of talking about hospitalized patients whereas Tamiflu would be the indication

(23:22):
there in blocks of year is only used in acute uncomplicated setting now finally just what
we have on formulary so in Tamiflu with Tamiflu it's a liquid and tablet that's available
and that's probably more beneficial for us pediatricians out there in terms of blocks
of year there's no liquid formulation that's available but they do have a tablet form unfortunately

(23:44):
cannot be crushed so considering that in your acute outpatient setting might be an important
me way in your decision when prescribing either of these antiviral agents definitely with
Tamiflu there was less side effects as we're quite aware with pretty safe drug less side
effects usually the side effects are nausea vomiting which get better with foods always

(24:08):
counsel your patients regarding that and then in the blocks of your group we discussed some
of the side effects again nausea gi upset were predominant but we're likely maybe encountering
more side effects in that with that agent compared to Tamiflu so that is basically what

(24:28):
I wanted to discuss today and as usual we are very grateful to have this podcast up
and running definitely would like everyone to reach out to us via email and let us know
what you're interested in listening to I would love to hear your thoughts your comments on

(24:51):
any of the episodes or any future episodes if you would personally like to come on to
the podcast and discuss an important infectious disease microbiology topic please do let us
know and thank you thanks for listening.
Thank you Dr. Purwall as well as Verity Pharmaceuticals for the generous sponsorship follow us on

(25:11):
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