Rheum to Breathe Journal Club Save

Rheumatology this month, September is ILD month and all month we've been featuring a lot of content on ILD and our Tuesday night rheumatology webinars have been discussions on ILD. I would refer you to the last two weeks, are on both YouTube and social media channels in RheumNow. But tonight we're going to do little differently doing a journal club. And we're going to discuss two pivotal articles as chosen by our advisory group. Let us introduce ourselves first.

I'm Jack Cush with RheumNow in Dallas, Texas. Sherwin.

Hi, I'm Sherwin Assassi. I'm director of division of rheumatology at UT Houston.

Doctor. Maguire. Doctor. Maher, sorry.

That's all right. So I'm Tobin Maher, I'm a pulmonologist and Director of the Interstitial Lung Disease Programme at the University of Southern California in Los Angeles. Before that, as we'll perhaps touch on later with the discussion of the RECITAL trial, I was in London at Imperial College in the Royal Brompton up until 2020.

Yeah, it's unconscionable that I get Toby's last name wrong when he's the lead author on both the papers we're going to discuss today. I'll pay some kind of penance for that later on. I'm going to start our presentation, by first, reminding you that these Tuesday night rheumatology webinars, are every Tuesday at 7PM. Tonight we're discussing journal, we're doing journal club. Next week, our final one, we'll have a session on diagnosis screening and monitoring of ILD.

I want to point you to RheumNow for all this content and thank our sponsor Boehringer Ingelheim. I want to acknowledge that the articles that we'll be discussing tonight in Journal Club, authored by, Doctor. Zasasi and Maher, both of them have been, advisors and consultants to Boehringer Ingelheim and the companies that make these trials and often been investigators in those trials. I too have been a consultant and therefore have a conflict of interest that you should be aware of. But to prepare for this TNR, do as we usually do a survey of rheumatologists and where your thinking is on these topics.

We sent out a one time email invite for this particular survey yesterday. Had two zero five responses, 86% of whom were rheumatologists, mostly from United States, seven percent were APPs. The topic here was that we would be discussing the Fiberonere New England Journal article and the recital, Lancet article. These are the two articles that are under discussion with Doctor. Maher as the lead author and a lot of very well known investigators.

These were pivotal trials as viewed by our advisors and that's why we're going to discuss them, this evening. But before I want to see what our panel thinks about the rheumatologist answers when I asked them which drug is not FDA approved for pulmonary fibrosis. Two thirds of them got it right, mycophenolate, fifty one percent, actually sixteen percent, and rituximab, fifty one percent. Those drugs are not FDA approved, but often used in patients with, pulmonary fibrosis. But a little bit of confusion, twenty one percent thought tocilizumab was not approved and, nine percent thought parfentadone was approved.

Sherman, do these results surprise you?

I think it depends whether this is a related question to systemic sclerosis or autoimmune pulmonary fibrosis in general. For example, tocilizumab is approved for SSC ILD, but not for other ILDs. Similarly, example, Perfanidone is approved for IPF, but not autoimmune ILDs that we deal with.

So Doctor. Maher, in your world, in the pulmonology world, I assume these are very well known facts, but in your talking about treatment for fibrotic lung disease, do you think that there's this degree of still a need for knowledge on the available therapies, the effective therapies?

Yes, certainly. I spend my time trying to raise awareness among my pulmonology colleagues as well of the different treatments. I think historically there has perhaps been an unhelpful divide between rheumatology and pulmonology because think as Sherwin said, tocilizumab for instance is approved for scleroderma ILD and I'm not sure many pulmonologists would have known the answer to that. I think we do need cross specialty communication and education to make sure we're all on the same page.

I've heard that over and over throughout the month. Rheumatologists are calling for it, pulmonologists are calling for We should certainly be reaching out to each other and developing those collaborations. We do that all the time with multiple specialties, including dermatology and GI. We certainly should be doing it in pulmonary and it should be pulmonary rheumatology clinics. I think there are in most major centers.

Are either of you aware of any?

I'll answer first and then Toby can take it from there, but we don't have a joint clinic because of the operational difficulties with that, but we do have a monthly interdisciplinary call with them where we discuss the cases. But many, many of my colleagues have already joined clinics where they see the same, they see the patient the same area. For example, the patient first seats the pulmonologist and then the rheumatologist. Patients tremendously benefit from that. I'll hand it over to Toby to see what is his experience.

Yeah, and it's something similar. I think both for reasons of reimbursement and the challenge of organizing clinics at the same time in the same place. We don't have a joint clinic in our hospital, but I spend a lot of time talking to my rheumatology colleagues. We spend a lot of time informally discussing the same patients and actually two of my rheumatology colleagues have clinics on the same day that I do. It's very common that the patients will see me and then see them or vice versa.

I think that's great when that happens. I asked a question about best indication for anti fibrotic therapy because we're going this way with our journal articles we're discussing today. The main answer was early progressive symptoms. The second most common answer in thirty one percent was high res CT findings, then damaged by high res CT and the least was investigator decision. I asked this question because these become, could these be the entry criteria into clinical trials?

We're going to get into that. There's a clinical trial reason for people to be enrolled. Is that the same as the reason in practice to start anti fibrotic, Toby?

I think for autoimmune ILD, the answer is not entirely clear cut. For the main disease that I see in my clinical practice, idiopathic pulmonary fibrosis, I think the answer is at diagnosis. But for CTD ILD, I think the answer is less certain. The patients that have tended to go into the clinical trials have been symptomatic patients, so they've had ILD and respiratory symptoms. In the tocilizumab trials, for instance, there was even greater selection of patients because they had to have active inflammation.

And as we'll discuss in Recital, we were including patients with disease that was considered to merit intravenous therapy. So it's not entirely clear cut based on the trials when the right time to treat is. My own view for the future is that we should be looking to prevent the development of ILD. I would hope that at some point in the not too distant future we will have the evidence to support early aggressive treatment of ILD so that we can prevent patients developing respiratory symptoms and respiratory failure. But as of today, I don't think we have the evidence to support that approach.

I want to remind our audience that you can ask a question at any time. Please put it in the Q and A box and we'll get to your question real time as you put it up. Certainly the panelists can ask each other questions. Sherwin, do you have one last comment on this?

So I think in our clinical practice as rheumatologists, we usually start with immunosuppression, but if there is progression and it shouldn't be early or late, if there is progression, we add on anti fibrotic. I think the reason for starting with immunosuppression is because we typically deal with systemic diseases where we have to control, for example, progressive skin fibrosis or inflammatory arthritis. And in those scenarios, our thinking is the immunosuppressive agents are more effective. But if there is any progression, I add on anti fibrotic and anti fibrotic should not be seen as a drug that is the purview of pulmonologists. We should own it slowly, co own it, not only alone, but own it together.

All the more the reason why we should cross pollinate and cross educate on the use of these drugs that most rheumatologists I think are not using but should. The guidelines have been out there, ACR guidelines. ATS also has recent guidelines. At UR in Barcelona, Anna Marie Hoffman Voalde actually presented these guidelines that were recently published on the treatment of CTD related ILD. You can see immunosuppressants are often used including rituximab, the role of entetanib and parfanidones have been defined, but cyclophosphamide really only having a small place in systemic cirrhosis with the most severe organ involvement.

This is a setup to why we're discussing, the two trials that we're going to discuss today. I do think that we need trials to help better define these guidelines because otherwise it's all conditional recommendations and expert opinion, which is a real limitation. And there's clearly been benefit from the earlier 2023 ACR guidelines with CHEST and then these most recent ERS, UR guidelines, and I think that they'll continue to get better. But what would the two of you like to see in guidelines going forward besides more clinical trials that help define?

I guess I'll start this time. I think there are some obvious gaps and that the clinical trial evidence is an important one. As everybody I'm sure is aware, most of the trial data is from patients with scleroderma associated ILD, and so the SSC ILD component of the guidelines is much more evidence based than any of the rest of it. There's very little data to support treatment once you go beyond SSC, and so a lot of it is either extrapolated from scleroderma, which I don't think is always the right thing to do, and a lot of it is based on expert opinion. I think we need to do a lot more work in developing the evidence and going beyond scleroderma.

I think as a pulmonologist, not all ILD is the same, and the different autoimmune diseases tend to have quite distinct lung phenotypes, to the point that I like to tease my rheumatology colleagues that you can actually diagnose the connective tissue disease from the CT scan, you don't need the autoantibodies. But the fact that you can actually have a stab at it means that there are different lung phenotypes go along with the different systemic phenotypes of these disorders, and even within myositis, the different autoantibody profiles also have different lung phenotypes. So, JO1 is different to PL7 is different to NDA5. So I think we need more evidence and we need more nuance, and as I alluded to with the last slide, I think we also need to change our approach in managing ILD. At the moment, we tend to shut the stable door after the horse is bolted.

I think to the future, need to develop the mindset of preventing disease rather than just trying to slow it or initiate therapy once patients are limited by symptoms.

Sherman, I'm going ask you a different question. You're really well known in the rheumatology community as an expert in scleroderma for your work at UT Houston, And we worry a great deal about scleroderma because we don't have enough tools, we don't have enough effective interventions. But to see these results as we have seen in the ILD trials, I think is really encouraging. How do you view it as a scleroderma expert who also is very interested in fibrotic lung disease?

So I was involved in that ACR chest guidelines that you just mentioned that was published last year. Just doing the literature review and reviewing it, I was amazed how much more evidence you have in SCC ILD compared to other autoimmune ILDs. So that is actually the success story of a community coming together, doing clinical trials. Initially, actually NIH funded clinical trials being Skademolang study one and two, but then also partnering with industry to do larger trials such as SENSUS to generate evidence. I think that can be done in other autoimmune ILDs and should be done as Toby mentioned.

I think for scleroderma, the evidence gap is we still don't know who would benefit from early on or upfront combination therapy. We also don't have sufficient clinical predictors and we need biomarkers to predict who would benefit from which type of therapy. For example, anti fibrotic versus something like mycophenolate that is going after adaptive immunity versus something like tocilizumab that is going after innate immunity. So, and then what was very evident from contributing to those guidelines is also we know very little about monitoring. We don't know who, how often should we do the PFTs.

We are just, these are just based on expert opinion. We don't know whether the PFTs should be done every four months, every six months, every year. We just come together and come up with a number, but this is not evidence driven.

Right,

okay. So next I want to go over clinical trials in ILD. The primary, what's what, and I'd ask the audience, what's the primary endpoint in an ILD treatment trial? Three quarters got this right in that usually FVC, twelve percent saying DLCO. And then we ask people in ILD patients who are entering clinical trials, should they stay on their background immunosuppressants or anti fibrotic?

The answer, again, three quarters said yes. Then we asked the same question about steroids. And almost sixty percent said they should stay on their steroids with most saying that you can go in on steroids, but you should be tapered. And then only about a quarter saying no. So I'll ask our panelists to address any one of these things about trial design, because I think our next slide is going to get into the clinical trials.

So I will start with steroids. It's a CILD person. When we wrote those guidelines, we didn't have hardly any strong recommendation, but there was, one of the few strong recommendation was not to give high dose steroids to SSC ILD patients. Right. And we see that again and again happening, And usually the patient is presenting to us with Skardema and Renal Crisis.

Yeah, that's what we don't want. We definitely don't want. Toby, is FVC always the primary endpoint in these trials?

So it has become the primary endpoint in the last decade or so, and really that's an extrapolation from idiopathic pulmonary fibrosis. In IPF, the FVC essentially is a surrogate for survival. The more rapidly your FVC deteriorates, the more likely you are to die in the short and medium term, and it has the advantage that it behaves very consistently across all levels of disease severity in IPF. It also has the advantage that if you're the trial sponsor, you can standardize the spirometry, you can standardize the device, and you can even look at the data that's generated and make sure that it's high quality. So for a number of reasons, FVC is a very good endpoint for IPF, and as a consequence, it's being carried over into the CTD ILD trials as well.

I think that's probably appropriate for scleroderma, although there are some wrinkles. FVC behavior changes based on disease severity and time from diagnosis in scleroderma, which is very different to IPF. Then in diseases like the myositis where the predominant abnormality, particularly early in the disease, is organising pneumonia, which is at least partially reversible, it's not entirely clear whether FVC remains a surrogate for survival. So a lot of the assumptions that we use from IPF don't necessarily carry forward to CTD ILD, but at the moment we don't have a better endpoint for assessing the lung. I think we're stuck with FVC, but we have to acknowledge that, first of all, we don't fully understand the dynamics in CTD ILD, and the dynamics of FVC may differ based on disease and underlying interstitial lung disease.

Yeah, that's the challenge, but I'm going to trigger Sherwin by saying it's better than the modified Rodman Skin score.

Well, and that's unfortunately one of the best things we have. So I'm going to get into the Fiber Near trial and I asked the audience for both the Fiber Near and Messiah to see if they knew the results of the trial right off the top of their head. The question was in progressive pulmonary fibrosis, those are the included patients in the FibroNir trial. Nirandomolast had a significant decline in FVC compared to placebo, and sixty percent said that's false and forty percent said that's true. And the article says treatment with Nirandomolus resulted in a smaller decline in the FVC than placebo over the forty two weeks.

So that was a takeaway on that. And then we also asked them, what's the MOA? What's the mechanism of action of this not yet FDA approved drug? Again, this article appeared in New England Journal, I think in June. Two thirds got it right in that it was an inhibitor of phosphodiesterase 4B, but still nineteen percent thought tyrosine kinase, which is the target of Nantenib, and fourteen percent pulled a rabbit out of their hat by implicating the NLRP3 inflammasome, which I'm unaware of a drug being studied in ILD targeting the inflammasome.

Let's get into the fibrinir trial. This was again from June 12. Doctor. Maher was the first and Doctor. Asasi the second author in this.

Here are the particulars. The goal of the trial was to see if this drug be under development would slow progression of pulmonary fibrosis. The drug itself is a inhibitor of phosphodiesterase 4B, thought to be both anti fibrotic and immunomodulatory. It's a Phase three trial with a equal randomization into three arms. The neuroendomolast eighteen milligrams BID or nine milligrams BID or matching placebo and patients were stratified to background therapies.

I'm going to ask for a comment here because, patients were not allowed to, they could be on immunosuppressants, but per rheumatologists, they're not on any immunosuppressants. They're not on cytotoxin, tocilizumab, mycophenolate, any of the drugs that we would use, they were not allowed to be on and hence that would mean most of the SARD related disease or CTD related disease was going to be excluded. But almost half, forty three percent were on a background of Nintedinib. They were allowed to be on prednisone up to fifteen milligrams and that could be adjusted afterwards after six months, I think, Overall, eighty nine percent completed. I'll ask for a comment on the rationale for that.

I think rheumatologists, we like combinations of things, but it would have muddied things up quite a bit, would it not?

I think it's worth thinking about who the population of patients in this trial are because I think it's particularly important for a rheumatology audience to then understand that so that they can interpret the data in the context of their practice. I'll perhaps give an overview of all of it and then I'm you're well placed to talk about the CTD, SAD, autoimmune, whatever we're calling it. You guys are as bad as ILD physicians for wanting to make your nomenclature complicated.

Yeah.

So first of all, progressive pulmonary fibrosis, what is that? So in ILD, we have patients with idiopathic pulmonary fibrosis who have a very distinct CT appearance in the absence of an underlying cause for their ILD. Progressive pulmonary fibrosis is then patients with any other form of pulmonary fibrosis, so that could be autoimmune related, so rheumatoid, scleroderma, myositis associated. Probably the biggest group in our clinical practice is patients with chronic hypersensitivity pneumonitis, so bird fancier's lung, farmer's lung, that sort of thing with fibrosis. Then because we enjoy confusing nomenclatures, we also have idiopathic NSIP, which is not a diagnosis that I like, but is a diagnosis that we're stuck with.

Essentially, that's the group who look and behave a bit like IPF, but don't have the classic UIP pattern on CT scan. And then to make it even worse, we also have the unclassifiable ILD, which is really the dustbin that patients get put into if they don't have IPF and they don't fit into any of the other groups, or for some reason we haven't been able to do a full set of diagnostic tests. So within the FibroNear trial, it was about twenty percent hypersensitivity pneumonitis, about twenty percent idiopathic NSIP, about twenty percent unclassifiable, and about twenty percent CTD ILD, and the remaining twenty percent were a mishmash of other things like sarcoidosis or industrial pneumoconiosis and things like that. So those are the patients. So from a rheumatology point of view, we're thinking about a twenty percent subset, which is where maybe, Sherwin, you can comment on how representative that twenty percent are given the no background immunosuppressive.

Sure. As was mentioned, mycophenolate, which is the most commonly used medication in this scenario in rheumatological practices was not permitted as background treatment. Although is the time frame and methotrexate were permitted, which is more commonly used in RA than in systemic sclerosis. And if you look at the diseases that were enrolled among SARD ILDs, the top disease is RA ILD followed by systemic sclerosis ILD and then others, which includes myositis, Sjogren, etcetera. So the reason why background mycophenolate was not permitted, because the thinking was one trial cannot answer all the questions.

So it's very hard most probably to permit anti fibrotic and then also mycophenolate. And then on top of that, in the initial trial to show a treatment effect. That's an evidence gap that can be addressed in follow-up trials. In terms of being representative, the majority of patients had UIP pattern, which is the typical pattern for RA ILD, but not for other SARD ILDs. So that is also something that needs to be kept in mind for future trials.

Having said that, if you look at treatment effect, those patients who had UIP versus non UIP pattern, the treatment effect was consistent in both groups.

Okay. So, the trial was a large trial, a one year trial of almost 1,200 patients with, ILD not IPF. They had to have at least 10% fibrotic change on high res CT with a decline of greater than 10% and, and a few other features that were in for enrollment. The primary, endpoint here was the main difference or the the difference between the treatment groups and placebo, and you can see that it was, sixty seven mls, which was very significant P001, and the actual absolute values for change in, as measured in mls was ninety eight versus eighty four, eighteen versus nine milligrams with both of those groups being significantly better than the change, which was much worse with placebo. Side effects were mainly diarrhea, was thirty seven percent with eighteen milligrams bid, thirty percent with nine milligrams bid, twenty five percent with placebo, but some of that has to be from the background of nintedinim.

We've heard, that this drug is going to be much better as far as GI tolerability, but it's hard. I can't tell from this trial because both drugs are in play. Toby, can you comment on that?

Yeah. This actually links us one question in the chat, which is the difference between Nerandomolast and Apremolast, which I think is useful just to consider at this point. Apremolast is also a PDE4 inhibitor that is used for treating psoriasis. There's another one called reflumolast, which is approved for the treatment of COPD. The difference between neurandomolast and these other two drugs is that neurandomolast is specific for PD4B, so there are four isotypes of PD4, A, B, C, D, imaginatively.

The type that is found in the gut tends to be D, whereas the type that is found in the lung and seems to play a role in inflammation and fibrosis in the lung is B. So the advantage that Neurodomolast has over other PDE4 inhibitors is that it's more specific for the receptor that we think is important for driving fibrosis in the lung and has much less of an impact on the receptor in the gut, which drives the GI side effects. So that was the theory going into the trials, and certainly what you said would be my interpretation of the data and my experience using the drug in the trials is that on its own, in the absence of Nintedanib, Narendromolast is actually very well tolerated and causes very few GI side effects. I think the diarrhoea that we saw was a mild additive effect on top of Nintedanib. As everyone will know from clinical practice, Nintedanib really is a challenge from a GI perspective because it causes such a high frequency of diarrhea with our patients.

So let me just go to show some clinical benefit here with these, two slides. This is the, change in FVC at week fifty two. First two bars being eighteen and nine milligrams BID. The third bar on the right is the placebo. Obviously, a significant difference for both, neurondomalast treated groups.

And the graph on the right, the smaller graph on the right are the same results, but now looking at patients that were taking background Nintedinib. There's another graph showing patients not taking background. To me, it didn't look like Nintedinib added much to this picture or wasn't really responsible as much for the results. What's your interpretation of these results?

So I will comment on this, but just going back to the diarrhea question, I think there is one important table in this paper and that's the supplemental table eight, where it looks at the rate of diarrhea in their endomilous monotherapy group, because that basically teases out the effect of Nintedanib. Right. And in our clinical practice, we are more likely most likely to add Nir endomilast on top of immunosuppression than adding Nir endomilast on top of Nintedanib. And there, the rate of diarrhea in the nine milligram BID was exactly like placebo. And then in the eighteen milligram BID is just 11% more than placebo compared, for example, to inbuilt where nintedronib costs 40% more diarrhea than placebo.

So data are reassuring. Going back to this, I think it's a little bit misleading to extrapolate from these data that basically nintedinib doesn't work. Look how much, these patients, in order to be enrolled in this trial, had to have progression on nintedinib. These are people who have been on average one and a half years on Nintedanib.

Right.

And had to have progression on this drug. And if you look at the proportion of patients who are on supplemental oxygen, it's much higher on the Nintedanib treated group versus Nintedanib not treated group. These are sicker patients. I mean, we would not have enrolled them into clinical trials. They were perfectly fine on Nintedanib.

Yeah, that's an important point. I'm glad you made that clear. Go ahead, Toby.

Yeah, just jump in and say what's been interesting, again, going back to idiopathic pulmonary fibrosis because that's where we've done most of our trials, is that since the approval of the anti fibrotic drugs parfanadone and nintedinib, we've seen a change in behaviour of patients in clinical trials. Before we had anti fibrotic drugs, the average placebo patient lost about two forty mils. Since we've had the approval of nintedin and befemidone, what we see is that placebo patients who are on no background treatment actually now have a slower rate of FEC declines, so they lose about 160 mls, which is similar to this group, while in IPF the patients on background anti fibrotic lose a higher rate of FVC, so they lose about 180, 190. Both groups importantly are losing less than placebo patients used to lose before anti fibrotic therapy happened or became available, but you've got this paradox that the background treatment seems to be associated with more aggressive disease behaviour, and I think the way of explaining that is that patients who are not on background anti fibrotic are a self selected group of patients who've chosen not to be on them or chosen not to tolerate the side effects, presumably because their disease is more indolent, while the patients who go into the trial on background anti fibrotic therapy have almost by definition failed treatment.

Because if you're succeeding on anti fibrotic drugs, you don't normally look to go into a clinical trial. I think one of the real challenges we have when it comes to assessing the effectiveness of anti fibrotic therapy in the individual patient is that we don't have an easy way of knowing how well treatment is working because if patient loses 200 mils while taking nintedinib, we don't know if that's success because they would have lost three hundred-four 100 mils without it, or whether it's simply an indication that the drug isn't working. So that's a real difficulty we have in our clinical practice, is making a decision about whether treatment is working or not for our patients.

Yeah, that's all I think, and we can see parallels with that in rheumatology as well over time. Response rates have changed, especially in placebo patients and untreated patients that confound, the clinical trial and their design. So here are the results as far as the, ML change over the one year, the top left being what happened in this Fibroneer trial. The gray bar being placebo dropping 160 plus mls, and the two doses of Narendoma last doing better. And then just for comparison, I grabbed a study, on entedinib, and this is in, I think, IPF patients, the impulsive study, and boy, they sort of look the same with nintedinib showing a similar kind of benefit.

And again, that bottom right trial is not, there are no rheumatology patients in that group at all. There's no CTD or ILD. I just wanted you to see what, Nintedin. So, fairly consistent effect with effective anti fibrotic therapy, maybe, a little better with some sicker patients in the top left. Any comment on this?

I guess I'll jump in quickly. I think there's a few interesting things. We just compare the placebo groups, they do look very similar, which I think is a reminder of the significant morbidity and potential mortality associated with progressive pulmonary fibrosis. That rate of FVC decline is very similar to what we see in IPF populations. As you've already shown, the mortality rate at twelve months was about eight percent in the placebo group.

It was actually about twelve percent by fifteen months when we've looked at data beyond the twelve month point. So more than one in ten patients are dying within the first year and a half after going into this study, despite meeting inclusion criteria, which really rule out comorbidities and other things. So this is a serious problem that we're dealing with. I would love to see true stability in that line, but we don't. Obviously, the hope is that in the general population some of those benefits may ultimately be additive, but I think, as Sherwin said, we had to start somewhere with the clinical trial, and it's a good problem to have that we now need to work out how these drugs might work together and how we might look to combine them in clinical practice, but there needs to be much more clinical trial research done to define the answer to that.

Sure, what strikes you about this data?

Two things. First of all, there is a very consistent finding between phase two, also the IPF and this trial, that there is an early bump within first two weeks. We have never seen that in any other trial. So the separation happens really fast, which is unlikely to be just anti fibrotic. It is most, in my humble opinion, most probably some sort of immunomodulation, most probably some sort of innate immunity modulation.

That remains to be seen, that's a speculation, but that finding is very consistent, that early bump. The second take here is exactly what Toby mentioned, and I would like to second that. The same way we have to help our pulmonary colleagues remember the name SARD ILD, we need to learn the word means a fibrosing ILD that is progressive. If a patient has had ten percent decline in the last twelve months, the mortality of that patient is very similar to an idiopathic pulmonary fibrosis patient. These are data that, observational cohort data that Toby has coauthored.

This is a serious condition, especially if you think that PFT is not an outlier, you can repeat it within a month, see whether it is a true decline, or get a high resolution chest CT. If the decline is real, you cannot sit on that. That patient has risk of dying. You have to do something about it.

These patients, I think they're the same as the rapidly progressing ILDs that you see with MDA-five myositis, right? I mean, that's a group you don't wanna have to deal with because their outcomes are horrible. Toby reminded us of the death rates, which were not good, but SAE rates, serious adverse events were the same across all groups and over thirty percent, that's really high. These people are sick, these are not easy trials. The outcomes are ugly.

And I'm not surprised that you extend them out and follow them out beyond the one year that the problems still are going on. Obviously we need more and more treatment. Let's get into recital. I asked the audience, what was your takeaway from the recital? In the recital trial, rituximab was not superior to cyclophosphamide in patients with CT ILD.

Again, recital was done because it was unclear about whether there's a lot of anecdotal reports of rituximab, a lot of people relying on cyclophosphamide in bad patients. Anyway, over eighty percent said that this was true, that it was not superior, and that was actually the design of the trial. So, RECITAL was published in Lancet in 2023 with again, Maher leading the way. This was felt to be a pivotal trial. Here the trial was designed as a superiority trial, and not as large a trial as what we saw with the five Brineer study, but is cyclophosphamide, or sorry, is rituximab superior to cyclophosphamide in patients who are at high risk?

Those with progressive CTD, associated ILD. This is a double blind randomized active control phase two trial rituximab standard dose one thousand, two doses, two weeks apart, cyclophosphamide six hundred milligrams per meter squared given every four weeks times six months, a pretty aggressive regimen. And the primary endpoint was the, FVC change at twenty four weeks. Secondary endpoints included DLCO walk time, quality of life, MD global, both at twenty four also at forty eight weeks. So the CTD ILDs were scleroderma, myositis and MCTD with scleroderma and myositis each having about forty percent each and about twenty percent with the mixed kind.

And the enrollment was having one of those diagnoses and then at investigator discretion, they were enrolled, meaning that they probably were symptomatic enough to get in. And the good news is that like the other study, over eighty percent completed the trial. The other study was eighty nine to ninety two percent, here it was over eighty two percent. Both groups in this study improved their FVC from baseline to week twenty four. And again, the unadjusted mean increase, was ninety nine mls for cyclophosphamide and ninety seven for rituximab.

This was not significant with a P of point 49. Those are the values there. Again, the, adverse events, and SAE rates were similar. SAE rates again were high thirty three percent with cyclophosphamide twenty nine with rituximab and deaths ranged from four to six percent in this trial. Any comment on this or I'll show some data, show some of the figures next.

I can tell you about the design compromises and the challenges. So yeah, this was a labour of love. It was enough to drive me from The UK to the sunshine of Southern California to recover. But this was funded by The UK equivalent of the NIH, which I say that because it's very different to running an industry trial. In industry trials, money is generally speaking not such a big issue and you can afford to do everything and have all the clinical trial luxuries.

With an NIH funded study, you're doing it on a shoestring and one has to make some compromises along the way. So the choice to design a superiority trial was really based on feasibility and numbers, and also because we lack the data to really design a non inferiority trial properly. To design a non inferiority trial, you need to know the range of values that you might expect the treatments to fall within, and we didn't have that data. And then to try and do it with the data we did have meant a much bigger study. So we ended up compromising and running a superiority study, knowing that there was a risk that rituximab might just look the same as cyclophosphamide, and so we might not quite have the data we wanted.

I think the other compromise, I have to say in my clinical practice, when I use rituximab, I tend to use it with background mycophenolate, so patients will be on mycophenolate for the duration of treatment. And increasingly as a standard, I would repeat treatment at six months. Because we were using cyclophosphamide as the comparator, we didn't think it was appropriate to use background mycophenolate, and trying to have placebos and everything else for mycophenolate just made the study too difficult. So we're really just comparing the rituximab on its very own to the cyclophosphamide, which I think is probably not how we would use it exactly in clinical practice. And then the reason we chose the twenty four week endpoint rather than the forty eight week primary endpoint was at week twenty four, we allowed patients to go on to whatever treatment the local investigator thought was appropriate.

So beyond week twenty four, patients could go on mycophenolate, they could even have rituximab, they could go on to methotrexate, whatever treatment their local investigator thought was appropriate. Then finally, that decision to enter the patients in the trial, the investigator discretion. We wanted to avoid being too dogmatic about the criteria that meant patients were included in the study. Again, Sherwin knows this very well, but one of the challenges is once you start having specific criteria, you have patients who would otherwise be very good candidates for your trial don't get in because they've had a 9.9% decline in FVC in the last year, not a 10% decline. So we really wanted to capture that group of patients where local physicians felt that it was appropriate to use either cyclophosphamide or rituximab, and so these were patients with severe disease.

The mortality rate speaks to that, but I can't tell you exactly what the criteria was for each patient to go into the study, and that was because we were trying to be pragmatic.

Okay, that's great, to orient us. Here's the primary endpoint was at twenty four weeks. On the bottom, you're seeing what actually happened in on top of such twenty four weeks. The bottom, you're seeing the extension of the outcomes out to week forty eight showing us no significant difference between these two treatment arms. Then the side effect profile, many, many things were looked at, really nothing.

I was a little surprised, I would have expected cyclophosphamide to look uglier in many ways and it really didn't in this trial. Any ideas as to why that might be or do we overstate the toxicities at least in the short term of cyclophosphamide?

I can certainly give another opinion. In The UK, we've tended to use cyclophosphamide intravenously, so giving pulse intravenous doses as we did in RECYCLE. SLS-one, as I'm sure everyone remembers, was actually using oral cyclophosphamide. I think in my limited experience of using oral cyclophosphamide, it truly is a hideous drug. IV cyclophosphamide does tend to be better tolerated.

It's fair to say we also gave patients Mesner before the infusion, so they didn't have haemorrhagic cystitis. We gave them ondansetron as anti nausea treatment for three days afterwards as well, so we were controlling any nausea. So we were giving cyclo in the best circumstances. I would also say that in my experience, one of the challenges with cyclophosphamide is it's very difficult to reuse it. Once patients have had their six doses, if you then repeat it a year later, patients get many more side effects with the second cycle.

It's almost as though it's cumulative that the more cyclophosphamide you've had, the more sensitive to side effects you are, whereas rituximab is fairly consistent across time. You can repeat dose it without any change in its tolerability profile.

So, Jack, I would like to add what Toby is saying is really important because we used to use Sacrifice one orally and the cumulative dose of one year of Sacrifice one orally versus IV is very different when you also do gene expression profiling, when we convert SCAR demo lung study to, for example, to SCAR T, the gene expression profiling of changes of oral cyclophosphamide are so much more prominent. It's really affecting the whole immune So that should basically not be used anymore. If you're using it, you should use it IV.

Yeah, I can endorse these comments about cyclophosphamide and how it shouldn't or should not be used. I'm going to end with this. I asked the audience about mortality rates in these two trials, not knowing if they're familiar or not. The right answer here is about five to seven percent, and that was the majority answer. So for playing who wants to be a millionaire, go with the phone a friend and or get an audience answer.

This was right at forty six percent. But still a lot of people were concerned that it could be higher ten to twelve percent and thirty six percent or even worse up to twenty percent by 14. But as we said, these are really sick patients with high rates of serious adverse events and not surprising mortality rates. That's got to be the downside in designing these trials, Toby, you want patients that are going to change and you want to show a difference in change, but this comes with this horrible risk of not just a serious adverse event and hospitalization, but maybe even death.

It gets back to the basic point that ILD is, I think, nowadays the worst complication of any of the systemic autoimmune rheumatic diseases, just to prove I know what SAD is. We've talked about renal crises, but we're a lot better at managing those than we ever were. Pulmonary hypertension used to be a real killer in this patient group, but we've got so many more treatments. We've got 20 plus treatments for pulmonary hypertension these days. So ILD has really jumped up the charts as the most important problem we have to deal with that drives mortality in this patient group.

You've got to remember that we're selecting patients for trials who we're hoping won't die. We've already filtered out the even worse ones. My clinical practice is always a little bit depressing for the death notices I get every week, and I'm really very keen to see us change that. That's the driver for doing all these trials.

I'm going tell an ugly story. I don't know, twenty years ago, I had a great patient, a successful businessman, always came in dressed in expensive shoes and suits, and he was starting to have some shortness of breath and I sent him to wonderful pulmonologist locally who told him, you have RA associated ILD, get your affairs in order, you may not be alive in five years. And I was just so upset and mad at this pulmonologist. But really, was wrong because he didn't die in five years, but he died in eight. Just to underscore what Toby has said here, but is there hope?

There are drugs that are in development. I asked which drug is being developed to treat pulmonary fibrosis, and I'll ask both of you to comment on what you're looking forward to, but of you, half of you got it right that Nirandomolast is being developed for ILD, profenadone is already approved as an anti fibrotic. Voplosporin and obenetuzumab are not in clinical trials to my knowledge, but I'll ask both of you to end with what are you looking forward to as a future therapy that might change some of these outcomes? Doctor. Assassi?

I think short term, I'm looking forward to having nirandomiras added to our therapeutic options, a medication that is anti fibrotic potential, so immunomodulatory that has less GI side effects than entedanep. In long term, we also involve in a clinical trial where is the basket trial where we are putting neuroendeminase on top of mycophenolate and other immunosuppressive agents. And in the long term, I'm looking forward to having more informed decision, be it biomarker or clinical factors that decide who would benefit from upfront combination therapy.

Doctor. Maher.

Yeah, I think I echo a lot of Sherwin's thoughts. Perhaps we talk to each other too much, but I certainly agree with everything he said. I started doing ILD twenty years ago. For the first ten years, really the only meaningful thing we could do for our patients was offer them lung transplant. In the last decade, we've seen positive trials for nintedinib, befenidone, tocilizumab.

We now have a number of drugs approved as treatments for different forms of ILD, and there are 20 plus drugs in development across all forms of pulmonary fibrosis, whether IPF or SAD ILD. Some of those are immunomodulatory, some of those are anti fibrotic, some are a bit of both. So, I'm optimistic that the next decade we should see several more drugs developed, which I think is exciting. Then, as I've already alluded to, I think we need to take a much more aggressive disease modifying approach, I often tell the story my grandmother died with rheumatoid arthritis and I just as a child remember the way her fingers pointed out to the side with her destructive arthropathy. You don't see that in rheumatoid arthritis anymore.

It's a completely different disease and that's where I'd really love us to get to with ILD, that we're not seeing patients turning up in clinic on oxygen, but instead we're doing a CT at diagnosis and we're essentially practising secondary prevention to stop them getting ILD. And then I think Sherwin makes a very important point about personalised medicine. I think it's unlikely that the same treatments are going to work for all patients across all diseases, and we need to get much better at being able to select at diagnosis what the best treatment for that patient is going to be. So, as both Shervin and I are biomarker aficionados, that should keep us in academic careers until we retire.

Very sage comments. Gentlemen, thank you very much for your review perspectives on these two important journal articles. I'll remind the audience next week, our final week, we'll be talking about diagnosis screening monitoring, including biomarkers alluded to here tonight. Thanks to Boehringer Ingelheim for their support of this September month on ILD. Take care everyone.