Hello, and welcome, everyone, to another episode of Palm Beach.

Today, we're excited to bring you another in our series of rapid fire up journal clubs.

We're gonna be discussing the fibroneer IPF trial, the antifibrotic neurandamalast in IPF that was published earlier this year.

I'm also excited because of two great guests we have returning to the podcast today to help us think through another paper in the ILD space.

First, we're being joined again by recurring guest, Robert Wharton, who's a Pulmonary Critical Care Fellow at Johns Hopkins and whose voice you may recognize from episodes on the Impulsus and the Stellar trials.

Robert, thanks for joining back.

Hey, Luke.

Great to be here again.

Good to see you.

And next, we're also thrilled to be joined again by Nicole Ng, who you also may recognize from our earlier episode on the IMPULSUS trials and from IPFs more broadly, our discussion there.

She's an assistant professor of medicine at Mount Sinai Hospital and is the associate director of the interstitial Lyme disease program for the Mount Sinai National Jewish Health Respiratory Institute.

Pedrain, thank you for joining us.

Thank you, Luke and Robert.

It's a pleasure to be back here again and speaking on this exciting topic with you, you guys.

Yeah.

I this is, an interesting paper, and I think caused a little bit of a stir too, as I understand it when it was first presented.

And so I'm excited to break it down for folk here and now, Robert, before we get too into the weeds of what happened, can you tell us like a little bit about what we need to know going into our reading of this paper?

What's the background info we need to know?

Absolutely.

Luke, I think what's important to know is that the treatments for idiopathic pulmonary fibrosis remain limited.

We have mnteninib and propanidone, which provide modest reductions in FVC decline and may reduce exacerbations.

The cost of some pretty significant GI side effects, other side effects, and these treatments were subsequently shown to extend to entity of progressive pulmonary fibrosis in the inbuilt trial.

We're now seeing widespread use in practice, but we still have a lot of work to do.

The FVC decline in IPF is not stopped, and there's a high degree of morbidity and mortality associated with it.

This trial is exciting because it's got a new kid on the block, neuroendomlast, which is a preferential PDE four b inhibitor that has both antifibrotic and immunomodulatory effects.

It showed promise in a phase two study that was published in the New England Journal in 2022 with no FVC decline in the treatment arm.

And so this is the follow-up phase three trial, and, we'll talk about a little bit how that was restructured.

Yeah.

Doctor.

King, is there anything else you feel like we should know going into this paper?

Yeah.

Thanks, Rob.

I think that was a good, background to where we are now.

We agree we don't have any treatments to reverse or stop the disease only to slow FVC decline, meaning patients will continue to progress.

The phase two trial results were very encouraging and exciting to suggest that potentially we could have something that could finally halt FVC decline and stop disease progression.

Alright, Robert.

Tell us a little bit about what they did.

What happened here in this paper?

Absolutely.

This was an industry sponsored double blind randomized placebo controlled trial at 332 sites in 36 countries.

Like other trials in the IDF field, the primary endpoint was changed from baseline and FBC after fifty two weeks.

They did an analysis with a mixed model for repeated measures, which kind of smooths out baseline imbalances and covariates and creates greater statistical power.

They had a key secondary endpoint, which was the time to first acute exacerbation, hospitalization for a respiratory cause, or death over the duration of the trial.

The data analysis was performed by statisticians at Borringer Ingelheim who sponsored the trial, and they had central adjudication of the diagnosis of IPF by imaging review as well as guideline concordant diagnoses by a multidisciplinary team.

Yeah.

I always appreciate when they're, especially in this space where it's so nuanced making like final diagnoses.

I always appreciate when they're explicit about how they're making those, the central review of scans and things.

You've talked a little bit about how they were thinking about the patients in the trial.

Who ultimately was included in this one?

So these are patients with IPF And using the imaging criteria that I described, again, central adjudication review, they could also be included if they had a indeterminate CT pattern and also some sort of a cryobiopsy or a surgical lung biopsy that was consistent with the diagnosis at the local site.

They excluded a couple of notable groups, so liver dysfunction, which included transaminases or biliary event elevations on labs or a diagnosis of cirrhosis, advanced CKD with a GFR less than 30, and some cardiac comorbidities, hypertension greater than one hundred and sixty over 100 in the last three months, an MI, CVA, TIA, or in satal angina in the last six months, and notably psychiatric comorbidities, so like, suicide attempt in the past two years, suicidal adhesion within three months, or severe depression.

And this is based off of as a corollary to the side effect profile of other PDE4 inhibitors, namely Riflumilast and ensifentrine, which carry warnings for these psychiatric conditions.

Yep.

I appreciate you just pointing that out.

I feel like that stuck out to me because I think it's not true for other anti fibrotic trials.

One of the benefits of having a different mechanism of action is maybe it'll be more effective or work differently for our patients, but also has a slightly different potential side effect profile.

So I appreciate you calling out those exclusion criteria.

Who ultimately ended up in the trial?

We've talked a little bit about what they were looking to include or exclude.

Yeah.

Their table one is over 80% male.

The mean age is 70, about two thirds former smokers, and the mean DLCO was fifty one percent predicted.

This was similar to, Impulsus, which was the earlier trial of nintedanib in APF.

And most of the patients were on background antifibrotic.

So forty five percent of them were on nintedanib and thirty percent to thirty three percent were on pirfenadone.

In terms of severity of illness, the mean FVC was 2.8 liters or seventy eight percent predicted.

And doctor Ying, I was hoping you could expand a little bit on how this is comparing to other trials in the field.

Absolutely.

So IMPULSIS was with Nintedive, and the ASCEND trial was with pirfenidone.

These trials were both done more than ten years earlier, published in 2014.

So most of that baseline characteristics, as you mentioned in terms of sex, age, smoking status, they were pretty similar as you have mentioned.

A a significant difference was that patients in the older studies on Impulseus and Ascend, they had a median time since diagnosis of about one and a half years compared to three and a half years in the FRYBONEER trial.

So you may think the patients in the Fibonier trial were sicker.

They've been suffering from this disease for a longer period of time.

But I think it's more because the landscape of I of IPF has evolved significantly over the past decade.

And I suspect the rationale for the longer duration is multifactorial, but likely driven by earlier diagnosis, which represents lead time bias.

So if you look at other parameters such as the PFTs, despite the longer time since diagnosis, fibronaire patients had similar to higher FEC and DLCO values.

That's really helpful context.

I mean, I feel like fits with what I'm admittedly in my relatively short time as a pulmonologist.

In my experience, I feel like people get so many more CAT scans than it feels like they did even five years ago now.

And I imagine we're just catching folks a little bit earlier for a, they get a CT of their belly and there's something at the base now, or nodules for lung cancer screening and we find some interstitial abnormality.

Absolutely.

I think that's definitely true that we're seeing more incidental diagnoses of ILDs, and then that's why we have this huge area of interstitial lung abnormalities that is also being intact as well.

Yeah, for sure.

If the ILAs that I still have not graduated yet, so I have time still to learn what to do with them, but.

So we're all still learning.

Yeah.

All right.

So Robert, do you mind telling us a little bit, what did they do?

What was the intervention?

Yeah.

This was pretty straightforward.

So they had about 1,200 patients, and they randomized them one to one to urine on the last eighteen milligrams BID or nine milligrams or placebo.

They stratify the randomization according to background and fibrotic use.

First of all, before going into the actual results, we should always look at the CONSORT diagram to help us understand how patients flow through this study.

There were discontinuations in all the trial groups, so about seventy out of three ninety in each group.

Most completed the fifty two week incarceration period.

And upstream of that, a pretty good proportion of patients who were assessed were randomized, which is reassuring that the study team wasn't cherry picking patients that they thought would benefit.

And so for the primary outcome, there was about a 60 to 70 milliliter difference in FVC between the placebo group and most of the higher and lower dose groups, which was significant at a alpha of 0.05.

This is a pretty similar effect size to the phase two, except that the baseline decline in FVC was higher such that nerondamilast didn't halt FVC decline as we thought it might based on a phase two trial.

Some other notes about the results is a drug interaction with profenadone and neurodomelast, such that the patients who were receiving background profenadone via the eighteen milligram dose to be effective.

Thank you for walking us through that.

The drug interaction portion is really interesting.

I know Doctor.

Ng, when we were talking about this paper earlier, this was a thing that you had some thoughts about and in particular, their figure two, which folks listening at home alone can take a look at this to follow along with us.

But would you mind sharing your thoughts on how this drug ever seemed to interact with profenadone and so with the dosing of nirandomolast?

So I think it's very interesting.

So when I first looked at figure two, it looks like there's a clean dose dependent relationship such that the Neurandemlast eighteen milligram had the lowest change in the FEC followed by the nine milligram and then the placebo.

But I think that this relationship is driven primarily by the effects of the interaction between pirfenidone and the nine milligram of nerandomolast because of that interaction rendering it ineffective and, therefore, attenuating the effects of the nine milligram dose because the nine and eighteen milligram dose appears to be pretty similar.

If you look at the other groups of patients, such as the patients not taking background antithyrotic therapy and those taking background entendib.

So, you know, patients on emprazenadone, the differences between the nine and eighteen milligram doses, there, there was no difference between those two groups.

Yeah.

That is really interesting.

And to your point here too, at at first glance, I don't think I initially appreciated why they had reported this, but now that we've talked to it and more, I'm glad they did.

The authors actually measured plasma trough levels of neuroendomolast at steady state and folks who had about a 50% lower level than others.

And it's a point well taken.

I think the eighteen milligram dose seems what I have seen folks using, but it does make me wonder whether the nine milligram dose works too.

All right.

And so Robert, would you mind telling us, we talked a little bit about the primary outcome, but I know they looked at some other things too.

Can you walk us through some of their secondary outcomes here?

Yeah.

And this is important because their P secondary endpoint again, was this tied to event analysis of first acute exacerbation, hospitalization for respiratory cause or death, and there was really no benefit seen.

No no harm seen, but no benefit seen to neuroendal to last, which was fairly disappointing.

This was a more patient centered endpoint.

And there are really no improvements in any of its components or in the proportion of patients with a large decline in FBC or DLCO.

And I'll kick it back to the two of you.

I have my thoughts, but why do you think it might be that we didn't see any improvement here?

Yeah.

So these secondary endpoints are not common.

And so that's why the composite was used.

I mean, we need large sample sizes on long durations of follow-up to detect such a difference if present.

A limitation to the study was that these events were not centrally adjudicated.

There was no difference found in the composite or in the event individual events in the IPF trial.

But in the fibrony or ILD trial, there was a trend favoring the randomized and the same key secondary endpoints, particularly with mortality.

And more recently, pooled analyses of the fibroneer IPF with the fibroneer ILD trials did show anomaly significant reduction in the risk of death by fifty nine percent in those on Neurandum last eighteen milligrams versus placebo.

So it sounds like you're an optimist.

Do you think that if we extended this out, if we had all the patients, we would show some more significant patient centered endpoints?

And I think so.

And it also makes me think of, by corollary to the our earlier discussion about impulses where they have this pooled analysis showing your reduction in acute exacerbations when you have enough data.

I think that's the optimistic reading and then the pessimistic reading would be that it truly doesn't affect anything other than FEC.

Yeah.

I am cautiously optimistic that as we go forward and we get more experience and data with this agent that hopefully we'll see some signals towards benefit in some of these things as well.

I think FEC decline is important, but it's a space where I think getting a win and one of those other things would be pretty meaningful.

All right.

And so we've talked a little bit about kind of the efficacy of the drug, but I think it's also helpful, especially on the topic of anti fibrotics that notoriously have side effects.

Thinking about the adverse events here, Robert, how did folks tolerate this?

We expected side effects in this trial, and they were common in all the groups, including the placebo group, but there weren't any more serious adverse events or fatal events or things that led to interruption of the trial regimen in the treated groups.

The most common side effect is diarrhea, occurred in forty one percent of the overall high dose group.

And then in the folks who were also taking intetinib, it was as high as sixty two percent, which seems unsurprising to me.

Doctor.

Hain, did you have anything else to add about the side effect profile?

Yeah.

Yes.

So I would add that most of these cases were of mild diarrhea that was manageable.

So expectedly with nirandamilast, those taking background and entendinib, they had the highest rate of diarrhea in sixty two percent.

Otherwise, about a quarter of patients developed diarrhea, whether they are on background profenidone or nothing.

The higher dose of the eighteen milligram did lead to more diarrhea with twenty six percent versus seventeen percent without background therapy.

But I would highlight most of these cases were mild.

In patients who were taking nintenib, thirteen percent of those on the high dose and two percent of those on the low dose had to discontinue treatment because of the diarrhea, and only one percent of patients needed to discontinue that on their random last 18 alone.

So in summary, much less diarrhea compared to prior antibiotics, especially in Atenib.

And when present, tends to be mild, manageable, and not necessitating discontinuation of therapy.

Modifying two factors are dose of nerandom last as well as concomitant antifibrotic use, but overall, fairly well tolerated.

Yeah.

That's good to hear.

I think one other nice safety signal to call out here, just given that it was part of those exclusion criteria we mentioned, and theoretically, could it be a risk, I should say, of neuroendomolast and not the other anti fibroducts is there was actually no difference in the rates of vasculitis, depression, and or suicidality between any of the groups either.

And agree the adverse events of special interests were not more common in the treatment arms.

And so, Robert, we've talked a little bit about safety and efficacy.

Can you speak to any of the quality of life outcomes for folks?

Cause I know that's also been a sticking point with some of our anti fibrotics as well.

For sure.

Here, the results for health related quality of life were truly neutral, that not in any subgroup.

Was there any significant difference?

And the other thing that was disappointing was that it declined across every metric in every single subgroup, just reflecting how serious of a disease that this is, and we need better therapies.

So unless we have a disease modifying treatment that is able to reverse or improve the underlying scarring, patients will continue to progress.

And unfortunately we won't see meaningful improvements in health related quality of life parameters because they aren't getting better.

Yeah.

And I would argue that's reflected here.

It did slow progression, but people still did progress.

And like we've mentioned, none of those measures of quality of life improved, which is a victory still.

And that it's an effective tool, not as, as maybe as robust, an outcome as we maybe hoped for based on some of the earlier, like phase two trials.

And so Robert, we've talked a little bit about the nitty gritty.

I'm curious, taking a step back, how you think about this paper and the results overall.

So just to summarize, we have a decrease in the magnitude of FVC decline without any evidence of benefit in any other meaningful outcome, including mortality, exacerbations, health related quality of life.

So then we have to wrestle with how much does this FVC decline matter.

To put this effect size into context, this is about half the reduction in FVC decline seen within 10 and m, so up to 65 mils per year.

And some of the benchmarks that that I read about were that five to 10% decline in absolute FPC over a year is associated with a hazard ratio of one point three four mortality, and a decline of more than 15% carries a much greater hazard ratio of zero point one.

So we are hoping that the reduction in FEC decline will eventually translate to a patient important outcome.

And I'll turn it over to you all.

I mean, do you guys think that is worth it?

Is that something we should be pursuing right now?

Yeah.

So I think it is.

I might be biased, but I think it is.

I think the effect size still is clinically meaningful, especially as we know that patients with IPF despite treatment still progress.

So anything we do that can further slow down to disease progression is meaningful.

And while it's tempting, it would be inaccurate to compare the absolute differences in the FEC whether with Ascend.

You can say that was roughly 200 cc's versus in Pulsus, roughly a 110 compared to fibroneer.

Even in the ASCEND and I in Pulsus IPF studies that occurred within the same time frame, the patient populations were quite different.

The baseline characteristics of patients in the ASCEND trial did have lower FPC and DLCLs than that of in Pulsus.

So I I actually like to look at the placebo groups and trials because it gives you a look at the natural history of the disease course and how patients recruited into the study at that time were doing without intervention.

The FEC decline in the placebo groups were about 400 cc's in ASCEND, two to 240 cc's in a pulse is one to c one to two, and a 150 cc's in fibroneer, which has the lowest rate of decline.

So perhaps patients in the FibroNIR trial were less sick as we mentioned before because of the differences in the PFT parameters and rate of FEC decline.

So I'd attribute these improvements to, like we said earlier, diagnosis lead time bias, but also improvements in standard of care that we have antibiotics referral to palm rehab, use of supplemental oxygen management of comorbidities, etcetera.

Yeah, that is a really helpful context.

And I do think, I mean, to me, this is, these are still compelling results.

So I think it seems in my mind to fit kind of a piece with the other NITFI products.

I am curious.

I know we can't quite compare them head to head, but I am curious, doctoring, how in your mind, how this kind of fits in context with some of the other trials, whether for the other agents, I should say.

Absolutely.

And this is the question everyone's asking.

And it's sort of a head to head trial.

We would have to consider these to be relatively similar, and we can't say which if one is better than the other.

I would say within each of these trials, the intervention did lead to a relative reduction in FBC.

This is hand waving maybe around 50%.

If you consider the numbers in a SEN, the the difference is 235 versus four twenty eight, and pulse is a 110 versus 200 to two forty ccs, and fibrinear 70 versus a 150 ccs if you're looking at the no background therapy group.

One additional point I wanted to bring up about figure two is that if you focus on these placebo groups once again, the change in FEC in the overall population was a 180 cc's.

So when you stratify it based on background of antifibrotic, the decline was lowest in those taking nintenib or profenidone at a 190 cc's compared to those non on anti fibrotic therapy at a 150 cc's.

In other words, at first glance, it almost looks like patients who are taking anti fibrotics had a greater decline in FVC than those not on therapy.

At first, it didn't make sense.

I was also considering the fibroneer ILD trial where the same trend happened on background entetinib.

It was a drop of 180 cc's versus one fifty without background therapy.

But here, it made more sense because patients in the fibroneer ILD trial, they had progressive pulmonary fibroids system.

They were selectively chosen to have progression based on FEC and or imaging and symptoms despite antifibrotics.

But here, in the fibroneer IPF trials, documented progression is not a requisite.

But ultimately, I do think patients on antifibrotics in both studies were more likely to have advanced the disease than those not on background treatment, what we call channeling bias.

I think this is supported by data in the supplementary appendix table f three, which is suggestive that patients on background antifibrotic were likely thicker with a longer time since diagnosis, lower PFT parameters, and increased use of supplemental oxygen.

I'm not sure that the differences are significant enough to yield the differences in the FEC outcomes we saw, but I think it does indicate that channeling bias is likely playing a role.

Yeah, that makes sense to me.

I think it was, I was also a little like taken aback that at first glance, it seemed like the folks who were on therapy did worse than folks on placebo, but it, I think the way you've framed it, I could find pretty convincing, that it's more that the people who were already doing worse or had more advanced disease are the ones who are gonna come into this trial and therapy, especially since they weren't being selected where everybody was progressive as a requirement to be enrolled in the first place.

That makes a lot of sense to me.

I think those are really important points.

And I guess that begs the question of where does that leave us now?

What are the gaps in the field?

And, specifically, I was wondering what you might think about or how you might think about first line therapy in people who are being considered for neuroendomelast because the trial itself doesn't necessarily stipulate that you have to start someone on another antifibrotic first, or should we be starting neuroendomelast first?

How are you thinking about that, Doctor.

Ng?

I'm still thinking about it.

Awesome.

Short of head to head trials, we can't say which medication is more effective.

In IPF, I would say all three antifibrotics are fair game.

My approach would be a shared decision making process with patients.

I probably favor Neurandemlast more for several reasons.

One thing we haven't discussed is that we don't need to do labs.

This is huge.

For patients, for providers, we don't have to bring them back after a couple of weeks and then do labs every three months.

And so I think that's a huge win for norandom last.

Secondly, GI side effects are significantly better with nerandom last than with mentenad.

Other considerations in terms of use, so prophenidone is used three times a day.

Some of my patients really don't like doing that.

And so all of these little things matter.

And so typically I would have this discussion with the patients.

And I think this also leads us to the next question of what is our approach to managing these patients if they're taking background therapy or if they're not taking background therapy.

Would you do upfront combination therapy or would you do add on therapy?

So I generally favor add on therapy because when a patient has side effects, you don't know which one it's from, and you just have to take a guess as to which one you'll peel back on.

But it does slow down the process to get patients on maximal medical therapy.

So I think similarly in this space too, I also have a shared decision making process and discuss the options to patients for a single antifibrotic versus combination antifibrotic as well as the different permutations of this because I think the patient's preferences are really important.

Some patients feel okay and they really don't like taking medications, can't convince them to take anything.

And then on the other end, you have patients who want to be as aggressive as possible and will take everything at once and a lot of patients fall in between them.

So I think that shared decision making is really key.

Yeah.

I love that.

I feel like more and more as I go through fellowship, the theme in pulmonary in particular, where we don't have the luxury of the 20,000 patient trials that the cardiology gets is shared decision making.

I feel like where these episodes always end.

So thank you for reminding me that patient first approach.

Yes, exactly.

So this has been a great discussion.

Thanks for bringing the paper to us, Robert.

As we wrap up here, I'm wondering what is your big picture takeaway from the FiberNeur trial?

What do you wanna leave our listeners with?

Yeah.

The top line result that I'll carry in my head forward is that neuron don't last as a new tool in our arsenal to slow the progression of IPF, Importantly worked alone or in combination of other endofibrotics with a favorable side effect profile, but it didn't improve mortality, exacerbations, or quality of life.

Yeah.

I love that.

Nice, succinct summary.

Doctor Ng, similarly, is there anything you wanna make sure that we take away from this conversation or from this paper?

In summary, I would say in a random last, as Rob has mentioned, was effective as monotherapy and as add on therapy in patients already taking background antifibrotic therapy who have idiopathic pulmonary fibrosis.

The recommendation is to start eighteen milligrams for all patients with idiopathic pulmonary fibrosis.

In those who incur side effects, namely GI, dose reduction to nine milligrams can be considered in those who are not taking background therapy or already taking nintenib.

But in those who are taking profenadone, dose reduction is not an option due to the drug infraction with nerandomlast rendering the drug ineffective.

A huge benefit though with nerandomlast is that lab monitoring is not necessarily compared to the traditional anti fibrotics, which is really important for our patients.

And while we still don't have anything to reverse or stop disease progression, I think we are moving in the right direction.

As I alluded to in the podcast last time when we discussed the INPULSIS trial, I do think the management of ILDs will require a multimodal approach akin to many other complex diseases from diabetes and hypertension to respiratory diseases such as asthma and COPD.

Nintedib and prophenidone slow down disease progression.

The addition of nerandomilast slows this down even more.

There continues to be numerous studies that are underway to continue to push the boundaries further towards more effective treatments.

Other trials have shown promise in phase two trials that halt a PC decline and even potentially improve it in trials such as the ELEVATE and WHISPLPF trials.

But more to come, and hopefully we'll have the opportunity to meet again with even more exciting updates.

Yeah.

I would love that.

Careful, what you promised, Doctor.

Ng, you're gonna find yourself very busy.

Problem to have.

We would love to have you back on both of you back on later, in the future.

All right.

Well, thanks everybody for listening.

Thank you to Robert and Doctor.

Ng for joining.

That's a wrap for today's episode.

I hope you all enjoyed it at home, and we will see you again soon for another episode.