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Hello, everyone. Today, I will be speaking to you about emerging therapies in pulmonary fibrosis care for 2025. Um, these are my disclosures available to you. And this is our assignment today, our learning objectives, and I'll leave those up for just a second. So let's move on to Mr. Rice today who has questions about if he can be treated. He listens to the diagnosis and after this, he's quiet for a bit. I've heard about the disease, doc. There's no treatment for this, right? But we're gonna reassure him today. Actually, we have now 3 options available that can slow the progression of IPF. So the first option um is the newest option. This is neurondomalasse. Neurondomalase is an inhibitor of phosphodiesterase 4B and via this mechanism, we may be able to differentiate myofibroblasts in the lungs. So as I said earlier, the fibroblasts begin to differentiate into myofibroblasts leading to collagen deposition, progressive fibrosis. The phosphodiesterase 4B pathway may be able to stop that differentiation and hopefully halt the fibrosis cascade. Um, it also interferes with other fibrotic signaling pathways such as TGF beta. That's a very important signaling pathway in the fibrosis process. And in a phase two trial, lung function was stabilized over a 12-week study with a favorable safety profile. So, neuronommaast went on to a phase 3 study. Patients were randomized in 3 groups, 18 mg of neurondomalast twice per day. Uh, 9 mg twice per day versus placebo. This is a pill. It's something oral, um, and background antifibrotics were allowed, so patients could take the other two FDA approved antifibrotic medications for IPF. That's, uh, nintentinib or crophenidone. Enrolled almost 1200 patients with IPF 40 years of age or older, and they had to have, you know, mild to moderate disease. Um, FBC greater than or equal to 45% are predicted and the diffusion capacity greater than or equal to 25% are predicted. And what we can see is you can see on the panel on your right that at 52 weeks, the progression of patients taking the 18 mg and indeed actually the 9 mg dose of neuronommala. Um, the progression was much slower than patients who were taking, who were not taking their endommalast. One little wrinkle to the study, just because this is the world we live in today, most of the patients were already taking antifibrotics. 77% of patients were already on some antifibrotic, either nitinib or perphenidone. So what about the combination of therapy? Well, First of all, I'll say that the study was not power to analyze subgroups. So this is a common question. What if I take two medications at one time, neuronommalast plus something else? Well, We cannot say with a high degree of certainty that the two medicines that two of the medicines together are better than one, but I think it's worth at least looking at some of the subgroups because they were published. These are patients that were taking nothing. So these are patients that, so you'll see the neuronommala 18 mg group and 9 milli group. These are patients on nothing else. Versus placebo, so nothing else at all. No background antifibrotics. The progression was quite slow, 80 cc, 70 cc's in 52 weeks. That is, that is a tremendous improvement in patients who weren't taking anything versus placebo 150 cc's in a year. What about taking Background tentativeb still made a difference. Um, and same thing with prophenidone still made a difference, but I will point out that in the 9 mg group, there was no difference with placebo and the speculation is that there's something about neuronommalat that interferes with the metabolism of prophenidone, perhaps metabolizes it more, uh, uh, more quickly than without neuronommalat. Therefore, the patients don't really get good therapeutic levels of the drug and therefore what came out of this study is that patients who are taking, um, Perphenidone and you say you want to add neurondomalas, you should not add the 9 mg dose to them because it's not really gonna make a difference. Whether truly combination of therapy is better than one versus one of the others is really an unknown question. So, prophenidone, the second of the three FDA approved medications, this was, um, studied in uh and published in 2014. Patients, 555 patients with IPF randomized to either oral prophenidone or placebo for one year. Prophenidone is a 3 times a day medication, so the dose was 801 mg taken 3 times per day. The endpoint was the change in vital capacity or death, a combination or composite outcome at week 52. And you'll see here that at um multiple um interval assessments at week 1326, 39, and 52, um, prophenidone slowed progression relative to patients not taking prophenidone and you can see the rate of change in FEC over 52 weeks was much better uh with patients taking prophenidone versus placebo and because of this prophenidone was approved for the treatment of IPF. The third option is nintentinib. Nintenib was studied in two parallel phase 3 trials published in 2014. There were a total of a little over 1000 patients with IPF randomized to either ninteninib, and the dose for nintentiib is 150 mg twice per day, another oral medication versus placebo. Primary endpoint was the annual rate of decline in vital capacity. In one year and you'll see again, as I mentioned, two parallel phase 3 trials in pulses 1 and in pulses 2, and in both of those phase 3 trials, the rate of change in FVC at 52 weeks was much slower in patients taking ninitib versus taking placebo. Therefore, ninitinib was approved to treat IPF in 2014. So again, we have 3 options now to treat our patients with IPF. What about progressive pulmonary fibrosis? Well, as of today, there is only one approved medication to treat progressive pulmonary fibrosis, and again, this is important because patients who begin to progress with their non-IPF ILD, they behave much like patients with IPF not taking anything. So we really need to um. Uh, appropriately address these patients as urgently as possible. So, this is the in-build study. This was a study of, uh, patients with progressive pulmonary fibrosis, um, over 52 weeks. IPF, as I said before, was excluded, and most background therapy was excluded. So if you have a patient who has, let's say, a connective tissue disease associated ILD, so oftentimes those patients are already taking some, you know, immunosuppressive anti-inflammatory medications. So those patients were not allowed in this trial. That's, that's an important point when we're thinking about what to do for our patients because if someone was already taking one of these medications, it's a little bit uncertain how much nit is going to help them, but it certainly is the only FDA approved option for them. 663 patients, half the patients had either exposure-related ILD, hypersensitivity pneumonitis, or a connective tissue disease associated ILD. More than half the patients had a UIP pattern and there was an improvement in patients' progression with progressive pony fibrosis. The progression indeed was slowed down if they took nunib versus taking nothing, and it really bore out whether they had a UIP pattern or not, as you can see here in the graph. So because of this, the FDA approved um intended to treat progressive pulmonary fibrosis.