Chronic Cough in ILD - Impact, Mechanisms and New Treatments on the Horizon

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All right, well,
while people are sort of trickling in,

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maybe we'll get started with tonight's
ILD master class called Chronic Cough in

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ILD - Impact,
Mechanisms and New Treatments on the

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Horizon.

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My name is Kerri Johannson and I'm a
pulmonary physician and a Interstitial

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Lung Disease Specialist at the University
of Calgary,

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and I'll be your moderator tonight.

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And it's my pleasure to moderate this
program and introduce you to tonight's

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speaker.

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So Doctor Imran Satia graduated in
medicine from the University of Cambridge

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in 2006,
at which now that I've been spending more

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time in the UK I realize it's a really
big deal.

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-- long time ago.

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He gained his membership for the Royal
College of Physicians and completed a

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specialist training in general internal
medicine and respiratory medicine in the

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North-West Deanery

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In 2017 he was awarded a PhD from the
University of Manchester in the

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mechanisms of cough in asthma and was
awarded the British Medical Association

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James Trust Award

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He was subsequently awarded the European
Respiratory Society Respire 3 Marie Curie

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Post-Doctoral Fellowship

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Dr.
Satia is currently on faculty at McMaster

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University in Hamilton and the Firestone
Institute for Respiratory Health.

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He consults on patients with asthma,
refractory chronic cough,

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complex airways diseases,
has broad research interests in

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understanding the mechanisms and
developing treatments for these

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troublesome conditions.

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So thank you so much for joining us.

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We're really excited to have you here
tonight.

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My pleasure, thank you.

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So we will go through a couple of
housekeeping items so you can feel free

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to turn your camera on or off for the
duration of the event.

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Everybody will be muted because in the
past we've experienced that sometimes,

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you know,
people unmute and then it's disastrous.

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Everybody will be muted,
which we could unmute if you want to

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during the Q&A session at the end.

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But likely we'll just keep the questions
through the chat box unless you have a

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really want to speak.

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So you can put questions in the chat
throughout the session, you know,

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if they're relevant,
we can always sort of stop and,

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and have some Q&A in the middle or we'll -- save all the

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questions for the end.

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And then at the end,
please do complete the evaluation form at

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the end of the session.

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We hope you find value in today's
unaccredited medical education program.

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We ask that you provide feedback again
with the evaluation form and the

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presentation is being recorded and will
be made available with slides after this

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evening's program.

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So we have disclosures of financial
interest.

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This program has received financial
support from Boehringer Ingelheim and the

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faculty have received honoraria for their
participation.

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The the faculty have been responsible for
developing all content in this learning

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activity.

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And in the spirit of balance and
integrity, here are the disclosures.

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So these are mine, and these are mine,
Doctor Satia's.

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And now it's my pleasure to pass things
over to Doctor Satia.

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First of all,
thank you very much to Boehringer for

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inviting me and for Kerri for moderating.

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It's actually surprising that in my 15
year research career,

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this is the first time I'm ever speaking
on Cough in ILD.

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So it was actually quite fun making the
slides because I I went back and looked

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at some of the old data and,
and when Boehringer asked me and

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Catherine asked me to give a talk.

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These are the five learning objectives
which I suggested. And to make it,

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as you know,
make it flow as logically as possible.

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And I want to talk about why and how do
we cough,

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explain the burden and impact of chronic
cough in patients with ILD,

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how to recognize potential ILD in
patients presenting with chronic cough,

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current treatments for chronic cough with
ILD and potential new treatments.

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So the most important question which I
want to first explain is why do we need

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to cough?

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And more importantly,
why might patients with ILD cough a lot

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which you will see a lot in clinic.

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So, you know,
cough is a really interesting symptoms

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because although we often say it is the
archetypal airway defensive reflex,

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the truth is, is that all of us anytime,
if we want to cough,

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we can cough right now.

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We can both voluntarily control it,
but it can also happen as a reflex when

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it's triggered by mechanical,
chemical or thermal stimulation.

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So if you swallow something the wrong way,
if you're exposed to smoke,

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even some people have perfumes, aerosols,
cleaning products,

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some people can be easily triggered by
their cough.

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So that's the first important thing to
bear in mind.

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And,
and the mechanisms of cough are quite

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complicated.

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And,
and I'm going to this is a paper that we

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recently published in a review article.

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But the important thing to remember is
that the cough reflex involves not just

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the afferent vagus nerves,
which is the C fibers and a delta fibers

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which line your throat and your chest up
in, in your trachea and in your airways.

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But the brain itself has quite important
ability to control those signals coming

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up.

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So sometimes you'll notice in the right
hand side,

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the top right panel is that when these
signals are coming up, they,

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they synapse in the brainstem and in the
brainstem.

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There is the opportunity here for what we
call central sensitization and there's

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various ways that can happen,
but there's also something else called

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impaired cough suppression or impaired
inhibitory control in the pain field.

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These are known as something called DNIC
or descending noxious inhibitory control.

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And this is a bit of a,
a weird thing to explain to people

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because I think central sensitization as
as medical students and physicians,

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we all kind of understand things being up
regulated.

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But one of the things you have to
understand about the brain,

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particularly when it comes to cough and
pain as well,

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is that there are constantly inhibitory
neurons which are firing right now inside

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of you.

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And these inhibitory neurons will
suppress things from activating the cough

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or even pain.

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And in cough,
we realized that actually those neurons

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might actually not be working properly
and therefore you lose the inhibition

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which should be there.

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And as a result,
all the signals that come up are just

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causing cough and often sometimes chronic
pain as well.

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And what's interesting is that these
inhibitory neurons,

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often on their nerve endings,
they will release endogenous opioids,

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dopamine,
sertraline and these neurotransmitters.

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The second thing I want to say is that in
the lungs itself,

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this is a picture at the bottom of an
airway epithelium.

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And the epithelium is lined by airway
nerves which pick up the signals in the

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epithelia

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But also there's some epithelial fibres
which are more mechanosensitive.

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So the C fibers generally are more
chemically sensitive and go to the

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epithelium.

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And the deeper ones,
what I call are the A delta,

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deeper for deep, D goes for deeper,
and they tend to pick up mechanical

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stimulation, mucus and phlegm.

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Now I'm going to point something out
which is a subtle point,

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is that this diagram that I'm showing you
and I've drawn is telling you about the

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epithelium.

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It's not telling you necessarily what's
happening in the peripheral lung

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parenchyma.

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Because what we do know is that as the
airways tree gets further and further

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away from the trachea,
that the nerves actually itself,

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they get fewer and fewer.

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And there is some debate in the
literature about how far do these nerves

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really get and whether or not in the lung
parenchyma, which is where fibrosis is,

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are,
are there are there actually any nerves

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seen there?

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So this is an area of ongoing academic
debate.

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So I hope you've understood why we cough
and how we cough.

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But the complicated question in ILD is
that why are people in ILD coughing?

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Why are people who have got pulmonary
fibrosis, why are they coughing?

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So this is just my basic diagram,
which is not basic at all,

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but this is how I think about when people
get referred to me with cough that I ask

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myself as an airways doc that is there
ongoing airway inflammation,

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Is there reflux?

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Is there really bad fibrosis?

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Is there traction Bronchiectasis and lots
of mucus and phlegm also associated with

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the cough?

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And is there hypoxia?

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Now hypoxia is an interesting one because
I often notice that many of our people,

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our patients who are coughing a lot don't
necessarily have desaturation or flying

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around or hovering around 88-90%.

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They often will have 94-96% oxygen levels,
which is, which is reasonable.

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But what I do find is that, you know,
the oxygen therapy that we give,

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it's very drying to the mucous membranes.

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And I often find that,
and this is completely anecdotal,

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is that the oxygen that they're inhaling
through the nose or their mouth is drying

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the mucous membrane and that changes the
osmolality of the lining.

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And that might trigger coughing.

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And I sometimes I've actually told people
to reduce the oxygen a bit and humidify

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and that can help.

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And finally,
in some of our patients with ILD,

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there is a,
there is hypersensitivity where the, the,

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the cough reflex arc from the periphery
and the central,

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that whole system that I've just
described that's become more

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hypersensitive.

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So the way I think about it is,
do I need to give anti-inflammatory?

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Do I need to give PPI?

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Do I just need to treat the fibrosis?

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Do I need to treat the bronchiectasis and
mucus and phlegm?

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Should I calm down on the oxygen and
humidify it?

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Or do I need to give something neuronal?

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And the point I want to make is that the
question is does targeting these improved

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cough.

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And I will say from the very beginning,
I don't have all the answers.

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So next question is what is the burden of
chronic cough in ILD?

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And you guys are all way more expert ILD
docs than I am.

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And ILD, as you know,
is a family of all sorts of fibrotic

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conditions,
but the common one being the IPF and the

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non-IPF.

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So I'm going to go back to 2011 where
Chris Ryerson published this paper in

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Respirology where he looked at 242
subjects with IPF and 84% of them

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reported cough.

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And what Chris did,
I think for the first time,

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and which is very important,
he first asked the question in a

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multivariate model,
is what are the factors that actually

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predict having cough.

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And you'll notice here that these are the
three independent things which predicted

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cough.

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So actually non-smoking.

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So ever smoked had a reduced odds of odds
of odds of cough.

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Exertional exertional desaturation
increased your odds of cough and having

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worse FVC percent predicted this is lower
because this is positive.

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So the worse your FVC the more likely you
are to have cough.

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He also then said that, OK,
does cough predict disease progression?

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So in this multivariate model,
he again proved and showed that cough,

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long term oxygen therapy and total lung
capacity all independently predicted

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disease progression.

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Here you will notice,
and I've deliberately put this,

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is that the definition of progression is
the old definition of 10% FVC decline and

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15% decline in DLCo or lung transplant
death or any cause.

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And then he looked at whether or not if
you have cough,

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does it independently predict death or
lung transplantation?

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And it wasn't quite positive, 0.08,
but it's,

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it's a trend being on long term oxygen
therapy.

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Obviously you would predict that because
these are people who are end stage and,

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and they're on oxygen.

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TLC,
lung capacity predicts it and also DLCo.

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But cough is the only symptom here,
at least which we've predicted had some

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relationship with with death and and lung
transplant.

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He did a separate,
separate Kaplan-Meier graph showing that

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over time on the X axis and the percent
survival.

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In the black line are those people whose
cough was absent and in the dashed line,

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sorry.

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In the in the dashed line is is the cough
was present.

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Sorry, in the in the yes,
the the dashed line is the cough was

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absent And in the,
the the black line here is the cough was

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present.

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And you can clearly see if we just take
50% as the median is that the curve is

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shifted to the right,
meaning that if you have cough in the

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black line,
your time to death is reduced slightly.

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It's not statistically positive in this
study,

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but there was showing a trend more
recently from the Canadian CARE-PF

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registry.

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They've also looked at IPF and non-IPF
and here I wanted to show this data just

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looking at the distribution of cough
severity VAS in IPF on the left and

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non-IPF on the right.

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And you'll notice here is that the median
is 24 in the IPF and 20 in the non-IPF.

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And I want to make some comments here.

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The first thing I want to point out is
that, you know,

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in refractory chronic cough,
when we see people who don't have IPF,

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often we recruit people who have got a
cough severity VAS around 40 and above.

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And in clinical trials they're often
about 65-70.

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And the point here which I was actually
quite surprised by is that there are some

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people with IPF and non-IPF that even 20
to 30% who say their cough severity Vas

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is 0.

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And I think this is quite interesting
because it clearly tells me that there is

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something unique going on in those people
who cough versus those people who don't

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cough which actually can provide a very
good signal.

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And this is what these authors did
published in the journals a couple of

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years ago is that what was the
association of cough severity with any of

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our clinical parameters that we routinely
measure.

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And you'll notice here there are no
surprises that lung function FEV, FVC,

00:14:32.598 --> 00:14:37.310
DLCo here we have also cardiac disease,
COPD, emphysema,

00:14:37.310 --> 00:14:41.360
although they weren't statistically
significant.

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GERD came out in this as well,
which we'll come back to in a second.

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And being on antifibrotic medication was
statistically associated with cough

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severity.

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But this is in a univariate analysis.

00:14:55.840 --> 00:14:56.880
So this is multivariate.

00:14:57.600 --> 00:15:02.000
And on the left hand side are the IPFs
and the right hand side are the non-IPFs.

00:15:02.600 --> 00:15:07.350
And one of the things that you notice
when you look at the ask the question,

00:15:07.350 --> 00:15:09.880
does your baseline cough severity matter?

00:15:10.520 --> 00:15:13.394
So here what they've done is you'll see
in the Red Arrows,

00:15:13.394 --> 00:15:15.880
I'm just focusing on the ones which are
important.

00:15:16.200 --> 00:15:22.118
if you have a baseline cough severity VAS
more more than 30 millimetres compared to

00:15:22.118 --> 00:15:23.880
less than 30 millimetres.

00:15:24.280 --> 00:15:27.472
Is your annualized change in FVC percent
predicted,

00:15:27.472 --> 00:15:31.893
your DLCo percent predicted your
development of disease progression and

00:15:31.893 --> 00:15:33.919
transplant survival, is it worse?

00:15:34.520 --> 00:15:39.467
And in all of those endpoints having a
cough severity VAS of more than 30

00:15:39.467 --> 00:15:43.680
millimetres is associated with worse
change in those outcomes.

00:15:44.240 --> 00:15:48.799
And if you look more carefully,
the coefficients in those people who have

00:15:48.799 --> 00:15:51.880
got IPF versus non-IPF,
the IPF seem to do worse.

00:15:51.880 --> 00:15:56.779
And this is what they wanted to show here
in this figure from the paper,

00:15:56.779 --> 00:16:02.014
which it seems to suggest that over time
in IPF patients compared to non-IPF,

00:16:02.014 --> 00:16:06.511
the gradient here is greater,
meaning that the the relationship is

00:16:06.511 --> 00:16:11.680
stronger and they tend to get more cough
over time compared to the non-IPFs.

00:16:14.080 --> 00:16:17.983
And then this is a paper from published
in the same year a couple of months later

00:16:17.983 --> 00:16:20.315
in the Blue Journal from Phil Molyneaux's
group,

00:16:20.315 --> 00:16:22.600
one of my colleagues at Imperial and
Jackie Wu.

00:16:23.040 --> 00:16:26.880
And they also looked at mortality based
on this 30mm cut off.

00:16:26.880 --> 00:16:32.033
And you don't need to be a statistician
here to realize that over time,

00:16:32.033 --> 00:16:35.754
if you have a cough severity VAS of more
than 30mm,

00:16:35.754 --> 00:16:41.480
your likelihood of survival actually is
significantly less significantly and it

00:16:41.480 --> 00:16:45.559
seems to be separating quite early on
within six months.

00:16:46.040 --> 00:16:51.309
So I do think the first point I want to
make to you guys is that cough is bad for

00:16:51.309 --> 00:16:54.073
IPF,
not just although the disease outcome

00:16:54.073 --> 00:16:57.736
measures that you guys measure in FVC,
DLCo, transplant,

00:16:57.736 --> 00:16:59.600
but also mortality and death.

00:17:00.280 --> 00:17:04.820
And I found this paper really interesting,
again from CHEST,

00:17:04.820 --> 00:17:10.180
that if you look at cough severity,
it's also associated with worsening

00:17:10.180 --> 00:17:14.200
productivity, work productivity,
activity impairment.

00:17:14.800 --> 00:17:17.984
It's not a perfect relationship,
it's a moderate relationship,

00:17:17.984 --> 00:17:19.400
but there is a relationship.

00:17:20.520 --> 00:17:24.799
You have to bear in mind though,
is that many of our patients who have ILD

00:17:24.799 --> 00:17:27.480
and IPF,
they'll be unemployed and not working

00:17:27.480 --> 00:17:27.880
anyway.

00:17:28.200 --> 00:17:31.226
And that's why you have lots,
those people who are lots of zeros at the

00:17:31.226 --> 00:17:33.160
bottom,
if you can notice that at the bottom.

00:17:35.360 --> 00:17:39.878
But they went on to do some univariate
and multivariate analysis to say what are

00:17:39.878 --> 00:17:43.840
the factors associated with work
productivity and activity impairment.

00:17:43.840 --> 00:17:50.444
And you can notice here at the bottom is
that dyspnea and cough severity and DLCO

00:17:50.444 --> 00:17:55.760
and FVC and oxygen all were associated
with loss of productivity.

00:17:56.520 --> 00:18:01.910
And then you when you put it into a
multivariate model and you'll notice here

00:18:01.910 --> 00:18:05.227
for the,
for the statisticians that this is a 0

00:18:05.227 --> 00:18:09.235
inflation model,
which means that what is the probability

00:18:09.235 --> 00:18:11.240
of not having any impairment.

00:18:11.840 --> 00:18:16.620
And what this shows is that the worsening
cough severity and the worsening dyspnea

00:18:16.620 --> 00:18:19.846
score you have,
the less likely you are to have no work

00:18:19.846 --> 00:18:20.480
impairment.

00:18:20.680 --> 00:18:23.074
In this paper,
they also did an incident rate ratio,

00:18:23.074 --> 00:18:25.423
which is a separate question underneath
this table,

00:18:25.423 --> 00:18:26.960
but I'm not going to go into that.

00:18:26.960 --> 00:18:29.805
And although this 3% and 4% might not
seem a lot,

00:18:29.805 --> 00:18:33.960
what you've got to remember this is cough
as a as a continuous variable.

00:18:34.280 --> 00:18:39.824
So a 1 millimetre change in cough
severity is associated with a 3% reduced

00:18:39.824 --> 00:18:43.520
risk or increased risk of having some
impairment.

00:18:43.760 --> 00:18:45.880
So a 10 millimetre is 30%.

00:18:46.920 --> 00:18:51.589
So you can see how small changes in
dyspnea and cough can have a big impact

00:18:51.589 --> 00:18:52.880
on work productivity.

00:18:54.560 --> 00:18:56.763
OK,
moving on to my next question is how do

00:18:56.763 --> 00:19:00.320
you recognize potential ILD in patients
presenting with chronic cough?

00:19:00.840 --> 00:19:04.929
So this is just my cheat sheet,
which you guys will know better than I

00:19:04.929 --> 00:19:08.500
will, that in my history,
I always ask about dry cough versus

00:19:08.500 --> 00:19:09.480
productive cough.

00:19:09.960 --> 00:19:14.591
And I'm also always worried when they say
to me that I also feel shortness of

00:19:14.591 --> 00:19:15.720
breath on exertion.

00:19:15.960 --> 00:19:19.099
And importantly,
I always ask that is the shortness of

00:19:19.099 --> 00:19:21.040
breath an independent to coughing?

00:19:21.440 --> 00:19:24.396
And the reason I ask that is because you
know,

00:19:24.396 --> 00:19:29.114
many people when they're coughing like -
- and they're going on and on and

00:19:29.114 --> 00:19:32.889
coughing a lot for 2-3 minutes at the end
of that coughing,

00:19:32.889 --> 00:19:35.280
it's expected to feel short of breath.

00:19:35.280 --> 00:19:37.338
I feel short of breath, but if they say,
well,

00:19:37.338 --> 00:19:40.842
the shortness of breath happens when I'm
walking, when I'm not coughing at all,

00:19:40.842 --> 00:19:43.120
then you know that there's something else
going on.

00:19:44.000 --> 00:19:45.920
I always ask about occupations.

00:19:45.920 --> 00:19:50.485
If you've been working in on shipyards
and painted decorators,

00:19:50.485 --> 00:19:52.080
have you got any pets?

00:19:52.080 --> 00:19:53.800
What kind of duvets you sleep on?

00:19:54.080 --> 00:19:56.560
Do you have any duck feathers and animal
feathers?

00:19:57.000 --> 00:19:59.800
Do you have dry eyes,
dry mouth and trouble swallowing?

00:20:00.560 --> 00:20:03.373
We have had, you know,
these are signs of connective tissue

00:20:03.373 --> 00:20:06.000
disease and I always examine for clubbing
- the joints.

00:20:07.080 --> 00:20:10.800
At McMaster we do have Nathan Martin and
Nader Khalidi.

00:20:10.800 --> 00:20:15.652
They have this clever little device which
you can measure or look at the length

00:20:15.652 --> 00:20:20.079
nailfold capillaries more carefully,
looking at the feeling the skin for

00:20:20.079 --> 00:20:23.293
Scleroderma,
looking at the mouth for telangiectasia

00:20:23.293 --> 00:20:25.720
and listening to the lungs for crackles.

00:20:26.320 --> 00:20:29.489
I think this is an important thing which
we often forget to do in clinic because

00:20:29.489 --> 00:20:29.920
we're busy.

00:20:30.240 --> 00:20:32.774
But I think if somebody's desaturating on
exertion,

00:20:32.774 --> 00:20:36.040
then that's a red flag for me that they
might have underlying ILD.

00:20:37.480 --> 00:20:40.320
Most of my patients do get full PFT,
get a chest X-ray.

00:20:40.320 --> 00:20:44.105
And when I do request the HRCT I will
request the inspiratory expiratory image

00:20:44.105 --> 00:20:45.160
with prone and supine.

00:20:45.440 --> 00:20:50.593
So these are the basic things that I tend
to do in anybody who I suspect might have

00:20:50.593 --> 00:20:52.680
ILD associated with chronic cough.

00:20:54.240 --> 00:20:54.720
OK.

00:20:55.800 --> 00:20:59.430
The next section is what about what are
the current therapeutic options in

00:20:59.430 --> 00:21:00.640
refractory chronic cough?

00:21:00.640 --> 00:21:03.876
And the first thing I want to talk about
is PPI,

00:21:03.876 --> 00:21:09.293
because about 15 years ago or 20 years
ago when I became a respiratory registrar,

00:21:09.293 --> 00:21:13.389
we were giving PPI's like candies and and
anybody with cough,

00:21:13.389 --> 00:21:18.542
anybody with ILD would just get given
omeprazole or lanzoprazole even without

00:21:18.542 --> 00:21:21.977
any reason,
even if they don't have any symptoms of

00:21:21.977 --> 00:21:22.440
reflux.

00:21:22.840 --> 00:21:25.960
I think all of you will now recognize
that that is actually changing.

00:21:26.520 --> 00:21:29.407
But the question is,
is that does the PPI therapy actually

00:21:29.407 --> 00:21:30.240
improve coughing?

00:21:30.840 --> 00:21:34.840
And we don't have any large RCT's,
but this is the only RCT that we have.

00:21:34.840 --> 00:21:39.840
So this is done by John Simpson's group
in Newcastle in England.

00:21:40.560 --> 00:21:47.991
And it's a small study where they gave 23
people omeprazole 20 milligrams twice

00:21:47.991 --> 00:21:51.800
daily or placebo for 90 days, so 20mg bid

00:21:51.800 --> 00:21:57.711
And the objective measurement here was
cough frequency and they did a bunch of

00:21:57.711 --> 00:21:58.160
PRO's.

00:21:58.360 --> 00:22:01.580
So the cough frequency here was measured
using the standard Vitalojak Cough

00:22:01.580 --> 00:22:01.920
Monitor.

00:22:03.880 --> 00:22:07.744
So this was the primary outcome result
and I'm going to talk you through this

00:22:07.744 --> 00:22:09.280
for and say a couple of issues.

00:22:09.680 --> 00:22:13.467
So the first point you'll notice here is
that whenever we do cough frequency

00:22:13.467 --> 00:22:17.354
measurements of the primary outcome,
we always use baseline or we do geometric

00:22:17.354 --> 00:22:17.600
mean.

00:22:17.600 --> 00:22:21.240
We log, we log,
transform the data into a log scale.

00:22:21.480 --> 00:22:23.957
And then when we want to get the value of
the mean,

00:22:23.957 --> 00:22:26.720
we calculate the geometric mean by going
backwards again.

00:22:27.840 --> 00:22:32.906
So you'll notice here is that at baseline
their cough frequency in the omeprazole

00:22:32.906 --> 00:22:36.120
group wasn't that high, 8.
2 and 9 coughs per hour.

00:22:36.640 --> 00:22:39.550
Just to give you an idea,
usually in our cough studies we recruit

00:22:39.550 --> 00:22:41.800
people who are coughing around 20 coughs
per hour.

00:22:42.600 --> 00:22:48.600
At the end of treatment it went from 8.
2 to 4.6. 9.1 in placebo to 8.3.

00:22:49.680 --> 00:22:55.248
So there was a ratio of around almost 40%
reduction in cough frequency,

00:22:55.248 --> 00:22:58.960
although this wasn't statistically
significant.

00:22:59.640 --> 00:23:03.442
And there was no significant difference
in awake cough frequency or nighttime

00:23:03.442 --> 00:23:06.319
cough frequency,
but there was some directionality but not

00:23:06.319 --> 00:23:09.440
enough to be statistically significant in
20 patients each way.

00:23:10.840 --> 00:23:13.550
You'll notice here even though they
recruited 23,

00:23:13.550 --> 00:23:17.400
they only were able to complete cough
monitoring in 20 in both groups.

00:23:18.320 --> 00:23:21.693
But then they also looked at the
Leicester cough questionnaire and other

00:23:21.693 --> 00:23:24.558
patient reported outcomes and
unfortunately none of them were

00:23:24.558 --> 00:23:25.760
statistically significant.

00:23:26.040 --> 00:23:29.597
There is another study which is ongoing
which I think they've started,

00:23:29.597 --> 00:23:31.000
which is a larger PPI study.

00:23:31.000 --> 00:23:35.040
But personally I'm not holding my breath
for PPI therapy.

00:23:35.200 --> 00:23:40.158
And as a result is I don't typically give
PPI therapy to everybody with cough and

00:23:40.158 --> 00:23:40.400
ILD.

00:23:41.080 --> 00:23:43.929
I only give it when they say, oh,
I have symptoms of heartburn and

00:23:43.929 --> 00:23:44.440
indigestion.

00:23:45.800 --> 00:23:51.207
And just last week this was data from the
CARE-PF registry where on the left hand

00:23:51.207 --> 00:23:56.285
side looked at cough severity VAS in
those people who have reflux disease or

00:23:56.285 --> 00:23:58.000
don't have reflux disease.

00:23:58.000 --> 00:24:01.869
And you can see that the median is
slightly elevated and it's statistically

00:24:01.869 --> 00:24:02.480
significant.

00:24:02.920 --> 00:24:06.076
But when you looked at people who were on
PPI or not on PPI,

00:24:06.076 --> 00:24:07.680
this is purely cross-sectional.

00:24:07.920 --> 00:24:09.560
It's retrospective cross-sectional.

00:24:09.800 --> 00:24:10.960
It's not prospective study.

00:24:11.280 --> 00:24:12.960
There was no difference in the cough
scores.

00:24:13.400 --> 00:24:18.341
And I've just copied and pasted this from
the conclusion that results of this large

00:24:18.341 --> 00:24:22.752
observational study suggest that the
concomitant presence of GERD does not

00:24:22.752 --> 00:24:27.517
have a major prognostic value in fibrotic
ILD despite GERD being associated with

00:24:27.517 --> 00:24:28.400
cough severity.

00:24:28.840 --> 00:24:34.726
These findings suggest that the PPI use
should be aimed primarily at symptom

00:24:34.726 --> 00:24:40.612
control - symptom control of reflux -
rather than suggesting any substantial

00:24:40.612 --> 00:24:42.600
impact on ILD progression.

00:24:42.600 --> 00:24:46.385
In this paper, if you go into detail,
there's lots of other secondary outcomes

00:24:46.385 --> 00:24:48.542
of FVC decline,
DLCo and other measurements,

00:24:48.542 --> 00:24:52.280
but I've just picked up on the on the on
the cough and reflux side of things.

00:24:53.920 --> 00:24:55.920
The next question is does azithromycin
work?

00:24:56.560 --> 00:25:00.975
So there has been a double-blind
randomized controlled placebo-controlled

00:25:00.975 --> 00:25:05.629
cross-over design study over 12 week and
they gave azithromycin 500mg Monday,

00:25:05.629 --> 00:25:08.672
Wednesday,
Friday and then there was a washout and

00:25:08.672 --> 00:25:11.000
then placebo Monday, Wednesday, Friday.

00:25:11.480 --> 00:25:13.360
And they did sequence A and sequence B.

00:25:13.360 --> 00:25:17.440
So you either get azithromycin first or
placebo first and you switch over and

00:25:17.440 --> 00:25:18.120
it's blinded.

00:25:18.640 --> 00:25:23.107
And it was a small study of only 20
people and the primary outcome here

00:25:23.107 --> 00:25:27.016
wasn't cough frequency,
but the Leicester cough questionnaire,

00:25:27.016 --> 00:25:28.320
the VAS and the SGRQ.

00:25:29.000 --> 00:25:30.440
And I'm going to show you the results.

00:25:31.560 --> 00:25:32.360
These are the results.

00:25:33.000 --> 00:25:37.458
You don't have to be a statistician to
realise that the results were completely

00:25:37.458 --> 00:25:37.960
negative.

00:25:37.960 --> 00:25:42.665
Now this raises the question is that they
gave this azithromycin to everybody

00:25:42.665 --> 00:25:47.672
indiscriminately and not really assessing
whether or not they have any evidence of

00:25:47.672 --> 00:25:49.120
neutrophilic bronchitis.

00:25:49.720 --> 00:25:53.407
So based on this,
some of my colleagues at McMaster and I'm

00:25:53.407 --> 00:25:57.218
involved distally with this study called
the SPECT ILD study,

00:25:57.218 --> 00:26:00.906
meaning that does measuring sputum
differential cell count,

00:26:00.906 --> 00:26:05.823
does it actually help or matter in terms
of treatment and does it actually help

00:26:05.823 --> 00:26:07.360
with with cough outcomes?

00:26:07.360 --> 00:26:08.640
So this is the SPECT ILD study.

00:26:08.640 --> 00:26:13.905
Ciaran Scallan is the PI along with
Terence Ho and Martin Nathan and myself

00:26:13.905 --> 00:26:15.360
are involved as well.

00:26:15.920 --> 00:26:20.909
So this is a randomized control study
where people get randomized to either

00:26:20.909 --> 00:26:24.520
sputum guided management or usual care
without sputum.

00:26:25.480 --> 00:26:30.196
And the benefit here is we are doing
questionnaires weekly or twice a week and

00:26:30.196 --> 00:26:33.360
also doing cough monitoring at the end of
the study.

00:26:33.840 --> 00:26:38.000
And this is the kind of algorithm that
we've developed.

00:26:38.000 --> 00:26:40.840
If you have eosinophilic,
then you get high dose ICS.

00:26:40.840 --> 00:26:44.309
If you have neutrophilic and you do
cultural sensitivity,

00:26:44.309 --> 00:26:47.720
then you give low dose azithromycin 250mg
3 times a day.

00:26:48.080 --> 00:26:50.495
If you have eosinophilic,
neutrophilic mixed,

00:26:50.495 --> 00:26:52.280
you get both ICS and azithromycin.

00:26:52.560 --> 00:26:54.800
And if you have paucigranulocytic,
then you get no treatment.

00:26:55.120 --> 00:26:59.360
So I think, and this is a larger study,
it's almost 125 patients.

00:26:59.360 --> 00:27:03.489
I think this will be a bit more
definitive in terms of understanding

00:27:03.489 --> 00:27:07.440
whether or not treating inflammation or
infection or combination.

00:27:07.840 --> 00:27:08.840
Is it actually useful?

00:27:10.760 --> 00:27:12.941
OK,
So you guys have been prescribing

00:27:12.941 --> 00:27:17.361
nintedanib and pirfenidone for a long
time and I wanted to find out and look

00:27:17.361 --> 00:27:21.781
back at the results from previous trials
on nintedanib that does nintedanib,

00:27:21.781 --> 00:27:26.143
even though it reduces FVC decline and
you guys know this better than I do,

00:27:26.143 --> 00:27:28.440
does it actually improve cough outcomes?

00:27:29.400 --> 00:27:34.064
And it just so happens that Marlies
published this a couple of years ago and

00:27:34.064 --> 00:27:38.426
she looked at the INBUILD study and
looked at the Living with pulmonary

00:27:38.426 --> 00:27:39.880
fibrosis questionnaires.

00:27:40.960 --> 00:27:46.334
And all of you will recognize that
because IPF is a progressive disease that

00:27:46.334 --> 00:27:51.080
as a result of that your symptoms are
going to get worse with time.

00:27:51.160 --> 00:27:56.847
And this is what we see in this light
blue colour in who had placebo is that

00:27:56.847 --> 00:28:01.796
symptoms of dyspnea, the total score,
fatigue score, impact score,

00:28:01.796 --> 00:28:04.160
everything gets worse with time.

00:28:04.840 --> 00:28:08.426
And this is in the total population.
In the blue bars,

00:28:08.426 --> 00:28:11.360
you'll see people who were given
nintedanib.

00:28:12.480 --> 00:28:16.662
And what's striking to me is that in this
group,

00:28:16.662 --> 00:28:22.040
the only symptom that really improved the
other way was cough.

00:28:22.280 --> 00:28:30.000
It went down compared to going up in the
other symptoms like fatigue and dyspnea.

00:28:30.360 --> 00:28:34.160
You'll notice that it did get worse,
but not as much as the placebo.

00:28:34.160 --> 00:28:36.720
So there was a what we call slowing down
effect.

00:28:37.120 --> 00:28:42.381
But the obvious thing here is the fact
that cough has actually got better in

00:28:42.381 --> 00:28:43.680
this questionnaire.

00:28:44.280 --> 00:28:47.643
And when they divided it by in those with
IPF,

00:28:47.643 --> 00:28:52.080
you can see in the IPF cohort is where
most of the signal is.

00:28:52.560 --> 00:28:55.680
And in the non-IPF cohort it wasn't as
significant,

00:28:55.680 --> 00:28:59.280
although you can see that the arrow bars
don't quite cross.

00:29:00.320 --> 00:29:03.560
So it got a bit worse,
but not as bad as the placebo.

00:29:04.600 --> 00:29:05.800
So this was interesting.

00:29:05.800 --> 00:29:08.511
So I thought, OK,
let me see if I can find anything on the

00:29:08.511 --> 00:29:10.120
other antifibiotic and pirfenidone.

00:29:10.520 --> 00:29:16.496
And this was published a while ago in the
ERJ, but this is not part of the,

00:29:16.496 --> 00:29:19.720
I couldn't find it from the RCT evidence.

00:29:20.040 --> 00:29:27.195
This is a before and after study where
they looked at investigated maybe 43,

00:29:27.195 --> 00:29:31.284
yeah,
43 subjects with IPF before and after

00:29:31.284 --> 00:29:32.400
pirfenidone.

00:29:32.400 --> 00:29:37.308
But here they did cough monitoring using
the Leicester cough monitor and they

00:29:37.308 --> 00:29:41.840
noticed that their cough frequency went
from 23 to 17, a 35% reduction.

00:29:42.360 --> 00:29:46.351
The LCQ improved by about two,
the MICD is 1.

00:29:46.351 --> 00:29:52.339
3 VAS improved by 19 and K-BILD
depression score did improve overall

00:29:52.339 --> 00:29:53.120
slightly.

00:29:54.200 --> 00:29:55.880
So this was a before and after study.

00:29:55.880 --> 00:29:59.678
It wasn't placebo-controlled,
but there was suggestion that they may be

00:29:59.678 --> 00:30:02.000
a signal to benefit having had
pirfenidone.

00:30:03.480 --> 00:30:08.732
I did recently look up the nerandomilast
study and I couldn't find the cough

00:30:08.732 --> 00:30:13.781
outcomes in the main manuscript,
but in Figure 7 or S10 in the supplement

00:30:13.781 --> 00:30:18.556
for those of you who want to look,
there seems to be no suggestion of

00:30:18.556 --> 00:30:23.400
improvement in the cough Living with
Pulmonary fibrosis questionnaire.

00:30:23.400 --> 00:30:28.253
Although I will caveat to say that as you
know, in the nerandomilast study, ,

00:30:28.253 --> 00:30:30.928
both studies,
people were allowed to be on

00:30:30.928 --> 00:30:31.800
antifibrotics.

00:30:32.440 --> 00:30:36.316
So one of the reasons why you might not
see it is that the benefit on the

00:30:36.316 --> 00:30:39.355
symptoms you're getting from the
pirfenidone, nintedanib,

00:30:39.355 --> 00:30:42.080
and there's no additional benefit of
nerandomilast.

00:30:42.080 --> 00:30:46.600
That's one explanation,
but there could be other explanations.

00:30:46.600 --> 00:30:50.844
I haven't seen the data sliced by being
on antifibrotic and not being on

00:30:50.844 --> 00:30:51.600
antifibrotic.

00:30:53.440 --> 00:30:57.554
Then we come to morphine,
which is published in Lancet Respiratory

00:30:57.554 --> 00:31:00.440
by Phil Molyneaux's group again and
Jackie Wu,

00:31:00.440 --> 00:31:04.800
where they took 43 IPF patients,
VAS of more than 30 FEC more than 45.

00:31:05.040 --> 00:31:08.413
And they did a double bland randomized
crossover design,

00:31:08.413 --> 00:31:12.320
5 milligrams twice daily of morphine
sulfate compared to placebo.

00:31:13.400 --> 00:31:14.440
And these are the results.

00:31:15.360 --> 00:31:18.612
So you'll notice here that those who were
given morphine,

00:31:18.612 --> 00:31:21.360
just look at again at the awake cough
frequency.

00:31:21.920 --> 00:31:22.400
We're not.

00:31:22.440 --> 00:31:24.798
You know,
if you remember that omeprazole study,

00:31:24.798 --> 00:31:27.589
their awake cough,
their cough frequency was about 8 or 9

00:31:27.589 --> 00:31:28.360
coughs per hour.

00:31:28.880 --> 00:31:31.000
Look at these people at 20-22.

00:31:31.000 --> 00:31:35.863
These are the typical patients that we
see in clinic and morphine reduced cough

00:31:35.863 --> 00:31:39.753
frequency down to about 10-12 coughs per
hour within two weeks,

00:31:39.753 --> 00:31:41.760
whereas placebo nothing happened.

00:31:41.760 --> 00:31:44.585
So the relative adjusted placebo
difference is about 39%,

00:31:44.585 --> 00:31:45.560
which is quite good.

00:31:46.560 --> 00:31:50.862
And there was statistical significant
improvements in cough severity,

00:31:50.862 --> 00:31:51.600
VAS and LCQ.

00:31:52.480 --> 00:31:55.355
Bear in mind that this was only for two
weeks,

00:31:55.355 --> 00:31:57.680
only for two weeks and and not longer.

00:31:57.680 --> 00:31:59.520
We don't know what the long term outcomes
might be.

00:32:01.520 --> 00:32:06.635
What about and and and they were given
this mainly because of inference from the

00:32:06.635 --> 00:32:09.920
non-ILD cough studies that suggests
morphine works.

00:32:10.440 --> 00:32:13.320
So this is an important study to show
morphine in ILD.

00:32:14.120 --> 00:32:18.640
So the next question is what about what's
the future for cough in ILD?

00:32:19.760 --> 00:32:24.688
So going back to my neurophysiology,
you know, this is the cough reflex arc,

00:32:24.688 --> 00:32:28.080
the peripheral nerve and the central
nervous system.

00:32:28.560 --> 00:32:31.000
And these are the peripheral antagonists.

00:32:31.160 --> 00:32:35.116
There's our P2X3 antagonists,
There's a TRPM-8 Agonist,

00:32:35.116 --> 00:32:36.600
which is -- the TRPA1

00:32:37.040 --> 00:32:40.600
There's sodium channel blockers which
block the action potentials moving across.

00:32:41.040 --> 00:32:43.869
And then there's morphine and nalbuphine,
which we're going to talk about in a

00:32:43.869 --> 00:32:44.120
second.

00:32:44.920 --> 00:32:49.704
But for this presentation,
I'm just going to focus on mainly the

00:32:49.704 --> 00:32:55.077
P2X3 and nalbuphine because the TRPA1
study failed in, in chronic cough,

00:32:55.077 --> 00:32:59.200
the TRPM-8 agonist,
we don't know the full results yet.

00:32:59.480 --> 00:33:02.960
Taplucanium is still running in Phase 2B,
but not in ILD.

00:33:03.520 --> 00:33:07.228
But most of the interest has been in
Gefapixant,

00:33:07.228 --> 00:33:11.240
P2X3 antagonist and camlipixant and also
nalbuphine.

00:33:11.560 --> 00:33:12.840
So I'm going to talk a bit about that.

00:33:13.920 --> 00:33:19.584
So gefapixant if some of you remember was
a the first in class P2X3 receptor

00:33:19.584 --> 00:33:23.263
antagonist,
which they did their whole program in

00:33:23.263 --> 00:33:28.560
basically refractory chronic cough,
not with pulmonary fibrosis or IPF.

00:33:29.200 --> 00:33:33.567
And they got to phase three and they had
two positive phase three studies,

00:33:33.567 --> 00:33:37.760
but FDA didn't approve, but Europe, UK,
Japan, Switzerland did approve.

00:33:38.040 --> 00:33:41.427
And in that time period about 5-6 years
ago,

00:33:41.427 --> 00:33:47.073
they also did a study looking at IPF led
by Fernando Martinez and it was a

00:33:47.073 --> 00:33:50.159
double-blind randomized crossover design.

00:33:50.760 --> 00:33:58.040
They gave gefapixant 50 milligrams twice
a day for 10 days and placebo for 14 days.

00:33:58.760 --> 00:34:02.101
There was a,
if you read the protocol carefully,

00:34:02.101 --> 00:34:07.489
there was a lots of problems with the
protocol because it it was changed after

00:34:07.489 --> 00:34:08.240
7 subjects.

00:34:09.000 --> 00:34:13.754
So initially, their protocol,
they wanted to give 50 milligrams for

00:34:13.754 --> 00:34:17.040
four days and then 150 milligrams for 10
days.

00:34:17.760 --> 00:34:20.672
In the end,
they changed it to 50 milligrams for 14

00:34:20.672 --> 00:34:22.240
days versus placebo 14 days.

00:34:22.240 --> 00:34:24.720
So that's one problem that you have 7
less subjects.

00:34:25.400 --> 00:34:30.229
The other problem is that there was a
technical error in the randomization and

00:34:30.229 --> 00:34:32.920
eight subjects didn't crossover as
planned.

00:34:34.040 --> 00:34:38.568
And the final issue is that remember I
told you that we always log transform

00:34:38.568 --> 00:34:42.509
cough counts for whatever reason,
they forgot in their sample size

00:34:42.509 --> 00:34:45.567
calculation to not log transform their
cough count,

00:34:45.567 --> 00:34:49.920
cough counts in the intention tree
analysis in in their statistical plan.

00:34:50.560 --> 00:34:52.880
So just bear that in mind what I'm going
to show you now.

00:34:53.360 --> 00:34:57.394
So on the top graph,
you'll see the intention tree analysis

00:34:57.394 --> 00:35:02.840
modified baseline to seven days to 14
days in the placebo and in the gefapixant.

00:35:03.480 --> 00:35:05.360
And you can clearly see there's no
difference.

00:35:06.080 --> 00:35:11.829
But when you then do the modified
intention with the natural log scale,

00:35:11.829 --> 00:35:15.902
although this is a log scale 10103
hundred coughs,

00:35:15.902 --> 00:35:20.693
there's some person here who's coughing
300 times per hour,

00:35:20.693 --> 00:35:26.443
There was a 24% reduction in cough
frequency compared to placebo with a

00:35:26.443 --> 00:35:28.359
nominal p value of 0.07.

00:35:28.960 --> 00:35:34.546
And when you do the responder analysis in
those people who had more than 20 percent,

00:35:34.546 --> 00:35:39.607
30%, fifty percent, 70% reduction,
you can clearly see that in this 20-30-50

00:35:39.607 --> 00:35:43.880
categories is that those who are given
gefapixant did do better.

00:35:43.880 --> 00:35:47.960
There were more people in that category
than in the placebo group.

00:35:48.160 --> 00:35:51.399
You would argue that maybe it's the 30
and the 50 who did the best,

00:35:51.399 --> 00:35:52.400
which is interesting.

00:35:53.280 --> 00:35:57.102
So although this is not available in
Canada or the US,

00:35:57.102 --> 00:36:02.591
it is it is available privately in UK,
Europe and other countries and and some

00:36:02.591 --> 00:36:07.803
people might be using this as private
prescriptions in those countries off

00:36:07.803 --> 00:36:09.680
label for ILD / IPF coughs.

00:36:10.760 --> 00:36:11.760
What about nalbuphine?

00:36:12.440 --> 00:36:16.137
So you know,
nalbuffine is an interesting molecule

00:36:16.137 --> 00:36:20.560
because it says that it's a kappa agonist
and mu antagonist.

00:36:20.920 --> 00:36:26.680
So this is all the typical pure opioid
agonists that we use.

00:36:26.680 --> 00:36:28.160
So we have morphine and codeine.

00:36:28.920 --> 00:36:34.040
So mu is the little red square and kappa
is the triangle.

00:36:34.680 --> 00:36:41.880
So morphine and codeine are pure mu and
kappa agonists.

00:36:43.840 --> 00:36:46.800
Naloxone is the opposite where we give it
to wake people up.

00:36:47.320 --> 00:36:49.240
It's a pure opioid antagonist.

00:36:50.720 --> 00:36:54.840
And then you've got buprenorphine,
which is mixed opioid agonist,

00:36:54.840 --> 00:36:58.400
and then you've got pentazocine,
which are mixed opioid.

00:36:58.400 --> 00:37:01.680
We don't use much of this,
but we tend to use the opposites.

00:37:02.160 --> 00:37:07.609
nalbuphine is an interesting molecule
because it seems to have activity against

00:37:07.609 --> 00:37:09.040
the kappa positively.

00:37:09.760 --> 00:37:14.076
So it causes analgesia,
decreased GI motility and sedation,

00:37:14.076 --> 00:37:19.040
but also supposedly it also has
antagonistic effects on the mu side.

00:37:20.160 --> 00:37:24.681
And the reason why this company has
developed this and reformulated this is

00:37:24.681 --> 00:37:29.440
because of this issue that it does not
cause respiratory depression or sedation

00:37:29.440 --> 00:37:31.760
because you're blocking this mu effect.

00:37:33.480 --> 00:37:38.242
And as a result of this,
the FDA don't regard this as a narcotic

00:37:38.242 --> 00:37:41.760
or a licensed sector - a scheduled
medication.

00:37:42.480 --> 00:37:46.275
So Anesis have been using this as an IV
formulation,

00:37:46.275 --> 00:37:52.077
but Trevi Therapeutics developed it as a
tablet and now it's been run in chronic

00:37:52.077 --> 00:37:53.080
cough studies.

00:37:54.160 --> 00:38:00.212
So this was the first 2a study in IPF,
Tobi led this study published in NEJM

00:38:00.212 --> 00:38:00.920
Evidence.

00:38:01.440 --> 00:38:04.200
And this was a double-blind randomized
crossover design.

00:38:04.320 --> 00:38:05.480
So just bear that in mind.

00:38:05.920 --> 00:38:12.301
And you'll notice here in the light grey
is that those people who were given

00:38:12.301 --> 00:38:16.610
nalbuphine,
they had a 75% reduction in their cough

00:38:16.610 --> 00:38:20.920
frequency, daytime and cough.
Placebo was 22%, 25%.

00:38:20.920 --> 00:38:22.920
And overall it's about 50% reduction.

00:38:23.880 --> 00:38:27.112
Now, remember,
Jackie Wu and Phil Molyneaux showed you

00:38:27.112 --> 00:38:28.960
can get about 40% with morphine.

00:38:29.480 --> 00:38:33.167
So Richard Irwin wrote an editorial on
this saying, hey, you know,

00:38:33.167 --> 00:38:37.680
you should do a study of nalbuphine with
an active comparator, which is morphine.

00:38:38.720 --> 00:38:42.040
But anyways, that is an ongoing question.

00:38:44.040 --> 00:38:47.300
But importantly,
you'll notice that people ask that in the

00:38:47.300 --> 00:38:50.228
paper that if, if the you know,
if you're improving,

00:38:50.228 --> 00:38:54.317
if you're taking this medication,
does it actually improve breathlessness

00:38:54.317 --> 00:38:54.760
as well?

00:38:54.760 --> 00:38:56.840
Because many of our patients are very
breathless.

00:38:58.040 --> 00:39:02.046
So here you'll notice at the bottom that
unfortunately nalbuphine it seems to act

00:39:02.046 --> 00:39:04.880
mainly on coughing and it doesn't improve
breathlessness.

00:39:06.320 --> 00:39:10.257
So based on that positive Phase 2A
crossover design,

00:39:10.257 --> 00:39:15.308
now they went into a Phase 2b dose
finding parallel group design to

00:39:15.308 --> 00:39:21.325
understand which is the right dose and we
want to give this drug for longer than

00:39:21.325 --> 00:39:22.440
just two weeks.

00:39:22.440 --> 00:39:25.327
So they went,
they had a blinded titration for two

00:39:25.327 --> 00:39:29.912
weeks and then fixed dose for four weeks
because you've got to titrate this drug

00:39:29.912 --> 00:39:33.366
up and they did Vitalojak cough monitor
0-2-4 and six weeks,

00:39:33.366 --> 00:39:36.480
which is the standard for regulatory
studies and PROs.

00:39:36.840 --> 00:39:40.480
So this was a study designed now going
into parallel group.

00:39:40.840 --> 00:39:45.419
One thing I will point out that whenever
we move from double-blind crossover

00:39:45.419 --> 00:39:49.404
design to parallel group,
we always lose a bit of efficacy because

00:39:49.404 --> 00:39:52.200
patients are not acting as their own
controls.

00:39:53.280 --> 00:40:00.280
So this was the reductions in cough
frequency at the different doses.

00:40:00.720 --> 00:40:07.680
So placebo 17-48-53-60 and relative to
placebo you're now getting?

00:40:08.240 --> 00:40:12.440
36% and 44%,
43% cough frequency reduction.

00:40:13.400 --> 00:40:18.513
And if you look at that over time,
what's quite interesting is that the

00:40:18.513 --> 00:40:23.840
improvement that you're getting is within
the first two weeks significant.

00:40:24.200 --> 00:40:29.000
When you're doing the dose titration up
between 2 and 6, you're on fixed dose.

00:40:30.960 --> 00:40:36.032
For sure 108 is the best,
but even 54 is not too bad and I'll

00:40:36.032 --> 00:40:39.960
explain to you why this might become
important.

00:40:41.480 --> 00:40:47.600
The LCQ also improved quite a bit by
almost 3.7-3.3 scores.

00:40:49.160 --> 00:40:53.090
And many of you will be using the LCQ or
have heard about it because it has three

00:40:53.090 --> 00:40:55.200
domains physical,
psychological and social.

00:40:55.520 --> 00:40:56.000
Social.

00:40:57.120 --> 00:41:02.240
But the issue of dosing is important for
this reason though.

00:41:02.240 --> 00:41:06.413
Although there was no deaths and no
serious adverse events,

00:41:06.413 --> 00:41:11.492
you'll notice here that the commonest
side effects are nausea, vomiting,

00:41:11.492 --> 00:41:13.440
constipation and drowsiness.

00:41:14.680 --> 00:41:15.200
So -

00:41:15.840 --> 00:41:18.640
These are the same side effects that you
would expect from morphine.

00:41:19.360 --> 00:41:24.878
And this is the thing which is bothering
me is that is it really a mu antagonist

00:41:24.878 --> 00:41:29.103
or is it really a partial mu agonist,
that if it wasn't that,

00:41:29.103 --> 00:41:33.600
then why are we still getting the nausea,
vomiting, constipation?

00:41:34.720 --> 00:41:37.880
And is a dose relationship up to 108.

00:41:37.880 --> 00:41:42.880
You'll notice it goes 14-37-50 that it's,
it's going up with the dose.

00:41:44.000 --> 00:41:46.968
Some would argue that oh,
you're getting these constipation,

00:41:46.968 --> 00:41:48.720
nausea because of the kappa agonism.

00:41:49.440 --> 00:41:51.240
I don't know to be perfectly honest.

00:41:51.240 --> 00:41:53.520
It could be, but it's still up for debate.

00:41:54.160 --> 00:41:58.778
So now based on this study,
they have enrolled and started a phase

00:41:58.778 --> 00:42:01.880
three study and I think the dose is not
108.

00:42:01.880 --> 00:42:03.240
I think they've got 2 doses.

00:42:03.240 --> 00:42:06.280
I think it's maybe 54 and something lower
than this and a placebo.

00:42:08.360 --> 00:42:14.236
There's another important point I want to
make is this is an amazing study for the

00:42:14.236 --> 00:42:19.901
IPF community with inhaled treprostinil
and some of you may have recruited into

00:42:19.901 --> 00:42:20.680
this study.

00:42:21.280 --> 00:42:25.400
And I want to make this point that
whenever we've done studies in asthma or

00:42:25.400 --> 00:42:28.871
any of the even cough studies and it
involves anything inhaled,

00:42:28.871 --> 00:42:32.016
even though you've got these amazing FVC
decline results,

00:42:32.016 --> 00:42:33.480
which are look pretty good.

00:42:34.320 --> 00:42:41.680
What you'll notice at the bottom is that
cough is the commonest adverse event,

00:42:41.680 --> 00:42:49.040
50% in the inhaled treprostinil versus
24% - double your cough adverse events.

00:42:49.080 --> 00:42:53.383
And the commonest reason for
discontinuation in of this medication,

00:42:53.383 --> 00:42:58.320
which seems to be very effective at
reducing the rate of FVC decline seems to

00:42:58.320 --> 00:42:59.080
be coughing.

00:42:59.280 --> 00:43:03.065
So I just want you to be aware of that
when if this ever gets licensed and

00:43:03.065 --> 00:43:07.052
approved that you're going to have to
manage the cough aspects of it in people

00:43:07.052 --> 00:43:08.920
who are already coughing quite a lot.

00:43:09.360 --> 00:43:11.720
So that's my bit of minor concern.

00:43:13.240 --> 00:43:16.209
OK,
so I'm going to stop there and I wanted

00:43:16.209 --> 00:43:19.718
to finish before 45 minutes past to just
say, look,

00:43:19.718 --> 00:43:22.080
I hope you understand why we cough.

00:43:22.480 --> 00:43:23.920
It's an airway defensive reflex.

00:43:23.920 --> 00:43:25.480
It's both voluntary and involuntary.

00:43:26.040 --> 00:43:29.232
Coughing is because of dysregulation of
the vagus nerve and the central brain

00:43:29.232 --> 00:43:29.560
process.

00:43:30.200 --> 00:43:34.080
Cough matters because it worsens quality
of life, prognosis and mortality.

00:43:34.960 --> 00:43:37.680
The old treatments do work like morphine.

00:43:38.040 --> 00:43:41.440
I will point out here to the audience
that people often ask me that.

00:43:41.440 --> 00:43:45.422
What about pregabalin,
gabapentin which we often use in RCC and

00:43:45.422 --> 00:43:45.920
non-IPF.

00:43:46.280 --> 00:43:47.600
Is there any evidence in IPF?

00:43:48.640 --> 00:43:51.310
There isn't,
but I still use it sometimes when

00:43:51.310 --> 00:43:52.560
everything else fails.

00:43:52.640 --> 00:43:53.840
So just be aware of that.

00:43:55.400 --> 00:43:57.280
Novel treatments, gefapixant

00:43:57.280 --> 00:43:59.720
It's approved in Europe and UK.

00:44:00.240 --> 00:44:04.344
I'm hoping that I can convince GSK who
have camlipixant,

00:44:04.344 --> 00:44:09.600
which is a new P2X3 antagonist,
will run a study in IPF in the future as

00:44:09.600 --> 00:44:11.040
as a new indication.

00:44:11.320 --> 00:44:15.360
And nalbuphine I think it's coming in the
next couple of years.

00:44:15.800 --> 00:44:18.986
So with that,
I'm going to stop and I'm going to hand

00:44:18.986 --> 00:44:23.824
it over to Kerri for question and answers
and discussion and any comments anybody

00:44:23.824 --> 00:44:25.240
wants to make, happy to.