1 00:00:17,655 --> 00:00:20,054 Hello, and welcome, everyone, to another episode of 2 00:00:20,054 --> 00:00:22,295 Palm Beach. Today, we're excited to bring you 3 00:00:22,295 --> 00:00:23,975 another in our series of rapid fire up 4 00:00:23,975 --> 00:00:26,635 journal clubs. We're gonna be discussing the fibroneer 5 00:00:26,775 --> 00:00:28,394 IPF trial, the antifibrotic 6 00:00:28,774 --> 00:00:29,274 neurandamalast 7 00:00:29,894 --> 00:00:32,406 in IPF that was published earlier this year. 8 00:00:32,406 --> 00:00:34,695 I'm also excited because of two great guests 9 00:00:34,695 --> 00:00:36,983 we have returning to the podcast today to 10 00:00:36,983 --> 00:00:39,272 help us think through another paper in the 11 00:00:39,272 --> 00:00:41,560 ILD space. First, we're being joined again by 12 00:00:41,560 --> 00:00:43,984 recurring guest, Robert Wharton, who's a Pulmonary Critical 13 00:00:43,984 --> 00:00:45,905 Care Fellow at Johns Hopkins and whose voice 14 00:00:45,905 --> 00:00:48,145 you may recognize from episodes on the Impulsus 15 00:00:48,145 --> 00:00:50,545 and the Stellar trials. Robert, thanks for joining 16 00:00:50,545 --> 00:00:51,045 back. 17 00:00:51,984 --> 00:00:53,664 Hey, Luke. Great to be here again. Good 18 00:00:53,664 --> 00:00:55,505 to see you. And next, we're also thrilled 19 00:00:55,505 --> 00:00:57,585 to be joined again by Nicole Ng, who 20 00:00:57,585 --> 00:00:59,770 you also may recognize from our earlier episode 21 00:00:59,770 --> 00:01:02,329 on the IMPULSUS trials and from IPFs more 22 00:01:02,329 --> 00:01:05,209 broadly, our discussion there. She's an assistant professor 23 00:01:05,209 --> 00:01:07,530 of medicine at Mount Sinai Hospital and is 24 00:01:07,530 --> 00:01:09,849 the associate director of the interstitial Lyme disease 25 00:01:09,849 --> 00:01:12,170 program for the Mount Sinai National Jewish Health 26 00:01:12,170 --> 00:01:13,310 Respiratory Institute. 27 00:01:13,745 --> 00:01:15,605 Pedrain, thank you for joining us. 28 00:01:16,704 --> 00:01:18,865 Thank you, Luke and Robert. It's a pleasure 29 00:01:18,865 --> 00:01:20,465 to be back here again and speaking on 30 00:01:20,465 --> 00:01:22,325 this exciting topic with you, you guys. 31 00:01:23,585 --> 00:01:26,064 Yeah. I this is, an interesting paper, and 32 00:01:26,064 --> 00:01:27,540 I think caused a little bit of a 33 00:01:27,540 --> 00:01:29,299 stir too, as I understand it when it 34 00:01:29,299 --> 00:01:31,459 was first presented. And so I'm excited to 35 00:01:31,459 --> 00:01:33,719 break it down for folk here and now, 36 00:01:34,260 --> 00:01:36,500 Robert, before we get too into the weeds 37 00:01:36,500 --> 00:01:38,500 of what happened, can you tell us like 38 00:01:38,500 --> 00:01:40,020 a little bit about what we need to 39 00:01:40,020 --> 00:01:42,625 know going into our reading of this paper? 40 00:01:42,625 --> 00:01:44,564 What's the background info we need to 41 00:01:45,104 --> 00:01:47,664 know? Absolutely. Luke, I think what's important to 42 00:01:47,664 --> 00:01:50,644 know is that the treatments for idiopathic pulmonary 43 00:01:50,704 --> 00:01:51,204 fibrosis 44 00:01:51,664 --> 00:01:54,484 remain limited. We have mnteninib and propanidone, 45 00:01:55,000 --> 00:01:57,799 which provide modest reductions in FVC decline and 46 00:01:57,799 --> 00:01:59,340 may reduce exacerbations. 47 00:01:59,959 --> 00:02:02,439 The cost of some pretty significant GI side 48 00:02:02,439 --> 00:02:05,000 effects, other side effects, and these treatments were 49 00:02:05,000 --> 00:02:07,819 subsequently shown to extend to entity of progressive 50 00:02:07,959 --> 00:02:11,064 pulmonary fibrosis in the inbuilt trial. We're now 51 00:02:11,064 --> 00:02:13,625 seeing widespread use in practice, but we still 52 00:02:13,625 --> 00:02:14,924 have a lot of work to do. 53 00:02:15,305 --> 00:02:18,824 The FVC decline in IPF is not stopped, 54 00:02:18,824 --> 00:02:20,664 and there's a high degree of morbidity and 55 00:02:20,664 --> 00:02:23,879 mortality associated with it. This trial is exciting 56 00:02:23,879 --> 00:02:25,239 because it's got a new kid on the 57 00:02:25,239 --> 00:02:26,299 block, neuroendomlast, 58 00:02:26,919 --> 00:02:27,979 which is a preferential 59 00:02:28,280 --> 00:02:29,659 PDE four b 60 00:02:29,959 --> 00:02:33,019 inhibitor that has both antifibrotic and immunomodulatory 61 00:02:33,639 --> 00:02:34,139 effects. 62 00:02:34,680 --> 00:02:37,365 It showed promise in a phase two study 63 00:02:37,365 --> 00:02:39,205 that was published in the New England Journal 64 00:02:39,205 --> 00:02:40,425 in 2022 65 00:02:40,884 --> 00:02:44,025 with no FVC decline in the treatment arm. 66 00:02:44,724 --> 00:02:47,284 And so this is the follow-up phase three 67 00:02:47,284 --> 00:02:49,604 trial, and, we'll talk about a little bit 68 00:02:49,604 --> 00:02:50,585 how that was restructured. 69 00:02:51,259 --> 00:02:53,019 Yeah. Doctor. King, is there anything else you 70 00:02:53,019 --> 00:02:55,099 feel like we should know going into this 71 00:02:55,099 --> 00:02:55,599 paper? 72 00:02:56,219 --> 00:02:57,739 Yeah. Thanks, Rob. I think that was a 73 00:02:57,739 --> 00:02:58,060 good, 74 00:02:58,939 --> 00:02:59,439 background 75 00:02:59,739 --> 00:03:01,979 to where we are now. We agree we 76 00:03:01,979 --> 00:03:04,060 don't have any treatments to reverse or stop 77 00:03:04,060 --> 00:03:06,859 the disease only to slow FVC decline, meaning 78 00:03:06,859 --> 00:03:08,854 patients will continue to progress. 79 00:03:09,314 --> 00:03:11,474 The phase two trial results were very encouraging 80 00:03:11,474 --> 00:03:14,354 and exciting to suggest that potentially we could 81 00:03:14,354 --> 00:03:17,155 have something that could finally halt FVC decline 82 00:03:17,155 --> 00:03:18,534 and stop disease progression. 83 00:03:19,330 --> 00:03:21,009 Alright, Robert. Tell us a little bit about 84 00:03:21,009 --> 00:03:22,689 what they did. What happened here in this 85 00:03:22,689 --> 00:03:23,189 paper? 86 00:03:23,969 --> 00:03:26,770 Absolutely. This was an industry sponsored double blind 87 00:03:26,770 --> 00:03:30,289 randomized placebo controlled trial at 332 88 00:03:30,289 --> 00:03:31,989 sites in 36 countries. 89 00:03:32,634 --> 00:03:34,974 Like other trials in the IDF 90 00:03:35,435 --> 00:03:38,634 field, the primary endpoint was changed from baseline 91 00:03:38,634 --> 00:03:39,455 and FBC 92 00:03:40,074 --> 00:03:41,375 after fifty two weeks. 93 00:03:41,835 --> 00:03:43,835 They did an analysis with a mixed model 94 00:03:43,835 --> 00:03:46,400 for repeated measures, which kind of smooths out 95 00:03:46,459 --> 00:03:49,840 baseline imbalances and covariates and creates greater statistical 96 00:03:49,900 --> 00:03:52,300 power. They had a key secondary endpoint, which 97 00:03:52,300 --> 00:03:55,520 was the time to first acute exacerbation, 98 00:03:56,139 --> 00:03:59,099 hospitalization for a respiratory cause, or death over 99 00:03:59,099 --> 00:04:00,319 the duration of the trial. 100 00:04:00,915 --> 00:04:03,555 The data analysis was performed by statisticians at 101 00:04:03,555 --> 00:04:04,455 Borringer Ingelheim 102 00:04:04,915 --> 00:04:06,455 who sponsored the trial, 103 00:04:06,915 --> 00:04:08,935 and they had central adjudication 104 00:04:09,395 --> 00:04:11,814 of the diagnosis of IPF 105 00:04:12,194 --> 00:04:13,335 by imaging review 106 00:04:13,669 --> 00:04:16,870 as well as guideline concordant diagnoses by a 107 00:04:16,870 --> 00:04:17,370 multidisciplinary 108 00:04:17,829 --> 00:04:18,329 team. 109 00:04:18,709 --> 00:04:21,509 Yeah. I always appreciate when they're, especially in 110 00:04:21,509 --> 00:04:24,790 this space where it's so nuanced making like 111 00:04:24,790 --> 00:04:27,689 final diagnoses. I always appreciate when they're explicit 112 00:04:27,750 --> 00:04:30,524 about how they're making those, the central review 113 00:04:30,524 --> 00:04:31,824 of scans and things. 114 00:04:32,285 --> 00:04:34,125 You've talked a little bit about how they 115 00:04:34,125 --> 00:04:36,305 were thinking about the patients in the trial. 116 00:04:36,444 --> 00:04:38,944 Who ultimately was included in this one? 117 00:04:40,365 --> 00:04:42,225 So these are patients with IPF 118 00:04:43,079 --> 00:04:44,540 And using the imaging 119 00:04:45,000 --> 00:04:48,379 criteria that I described, again, central adjudication review, 120 00:04:48,839 --> 00:04:50,839 they could also be included if they had 121 00:04:50,839 --> 00:04:51,740 a indeterminate 122 00:04:52,199 --> 00:04:55,000 CT pattern and also some sort of a 123 00:04:55,000 --> 00:04:55,500 cryobiopsy 124 00:04:55,959 --> 00:04:58,375 or a surgical lung biopsy that was consistent 125 00:04:58,375 --> 00:05:00,235 with the diagnosis at the local site. 126 00:05:00,615 --> 00:05:03,175 They excluded a couple of notable groups, so 127 00:05:03,175 --> 00:05:04,074 liver dysfunction, 128 00:05:04,535 --> 00:05:07,415 which included transaminases or biliary event elevations on 129 00:05:07,415 --> 00:05:09,355 labs or a diagnosis of cirrhosis, 130 00:05:10,420 --> 00:05:12,839 advanced CKD with a GFR less than 30, 131 00:05:13,220 --> 00:05:15,240 and some cardiac comorbidities, hypertension 132 00:05:16,020 --> 00:05:17,460 greater than one hundred and sixty over 100 133 00:05:17,460 --> 00:05:19,720 in the last three months, an MI, CVA, 134 00:05:20,339 --> 00:05:22,580 TIA, or in satal angina in the last 135 00:05:22,580 --> 00:05:26,324 six months, and notably psychiatric comorbidities, so like, 136 00:05:26,564 --> 00:05:28,964 suicide attempt in the past two years, suicidal 137 00:05:28,964 --> 00:05:31,064 adhesion within three months, or severe depression. 138 00:05:31,444 --> 00:05:33,685 And this is based off of as a 139 00:05:33,685 --> 00:05:36,805 corollary to the side effect profile of other 140 00:05:36,805 --> 00:05:37,305 PDE4 141 00:05:37,925 --> 00:05:38,985 inhibitors, namely 142 00:05:39,349 --> 00:05:39,849 Riflumilast 143 00:05:40,229 --> 00:05:43,209 and ensifentrine, which carry warnings for these psychiatric 144 00:05:43,269 --> 00:05:43,769 conditions. 145 00:05:44,470 --> 00:05:46,310 Yep. I appreciate you just pointing that out. 146 00:05:46,310 --> 00:05:47,669 I feel like that stuck out to me 147 00:05:47,669 --> 00:05:50,149 because I think it's not true for other 148 00:05:50,149 --> 00:05:52,470 anti fibrotic trials. One of the benefits of 149 00:05:52,470 --> 00:05:54,550 having a different mechanism of action is maybe 150 00:05:54,550 --> 00:05:57,415 it'll be more effective or work differently for 151 00:05:57,415 --> 00:05:59,735 our patients, but also has a slightly different 152 00:05:59,735 --> 00:06:02,454 potential side effect profile. So I appreciate you 153 00:06:02,454 --> 00:06:04,394 calling out those exclusion criteria. 154 00:06:05,254 --> 00:06:07,175 Who ultimately ended up in the trial? We've 155 00:06:07,175 --> 00:06:08,615 talked a little bit about what they were 156 00:06:08,615 --> 00:06:10,314 looking to include or exclude. 157 00:06:11,009 --> 00:06:14,930 Yeah. Their table one is over 80% male. 158 00:06:14,930 --> 00:06:16,229 The mean age is 70, 159 00:06:16,849 --> 00:06:19,409 about two thirds former smokers, and the mean 160 00:06:19,409 --> 00:06:21,589 DLCO was fifty one percent predicted. 161 00:06:22,050 --> 00:06:24,629 This was similar to, Impulsus, 162 00:06:25,394 --> 00:06:27,814 which was the earlier trial of nintedanib 163 00:06:28,194 --> 00:06:29,095 in APF. 164 00:06:29,795 --> 00:06:32,055 And most of the patients were on background 165 00:06:32,115 --> 00:06:34,115 antifibrotic. So forty five percent of them were 166 00:06:34,115 --> 00:06:36,274 on nintedanib and thirty percent to thirty three 167 00:06:36,274 --> 00:06:37,495 percent were on pirfenadone. 168 00:06:38,379 --> 00:06:40,060 In terms of severity of illness, the mean 169 00:06:40,060 --> 00:06:42,939 FVC was 2.8 liters or seventy eight percent 170 00:06:42,939 --> 00:06:43,439 predicted. 171 00:06:43,899 --> 00:06:45,819 And doctor Ying, I was hoping you could 172 00:06:45,819 --> 00:06:47,579 expand a little bit on how this is 173 00:06:47,579 --> 00:06:49,439 comparing to other trials in the field. 174 00:06:50,139 --> 00:06:53,264 Absolutely. So IMPULSIS was with Nintedive, and the 175 00:06:53,264 --> 00:06:54,645 ASCEND trial was with pirfenidone. 176 00:06:55,185 --> 00:06:57,264 These trials were both done more than ten 177 00:06:57,264 --> 00:06:59,845 years earlier, published in 2014. 178 00:07:00,384 --> 00:07:02,405 So most of that baseline characteristics, 179 00:07:02,785 --> 00:07:04,865 as you mentioned in terms of sex, age, 180 00:07:04,865 --> 00:07:06,865 smoking status, they were pretty similar as you 181 00:07:06,865 --> 00:07:07,605 have mentioned. 182 00:07:08,720 --> 00:07:11,120 A a significant difference was that patients in 183 00:07:11,120 --> 00:07:13,920 the older studies on Impulseus and Ascend, they 184 00:07:13,920 --> 00:07:15,939 had a median time since diagnosis 185 00:07:16,319 --> 00:07:18,420 of about one and a half years 186 00:07:18,879 --> 00:07:20,720 compared to three and a half years in 187 00:07:20,720 --> 00:07:23,444 the FRYBONEER trial. So you may think the 188 00:07:23,444 --> 00:07:25,845 patients in the Fibonier trial were sicker. They've 189 00:07:25,845 --> 00:07:27,764 been suffering from this disease for a longer 190 00:07:27,764 --> 00:07:30,564 period of time. But I think it's more 191 00:07:30,564 --> 00:07:33,524 because the landscape of I of IPF has 192 00:07:33,524 --> 00:07:36,660 evolved significantly over the past decade. And I 193 00:07:36,660 --> 00:07:39,079 suspect the rationale for the longer duration 194 00:07:39,459 --> 00:07:40,199 is multifactorial, 195 00:07:40,899 --> 00:07:43,399 but likely driven by earlier diagnosis, 196 00:07:44,100 --> 00:07:46,339 which represents lead time bias. So if you 197 00:07:46,339 --> 00:07:48,759 look at other parameters such as the PFTs, 198 00:07:49,394 --> 00:07:52,694 despite the longer time since diagnosis, fibronaire patients 199 00:07:52,754 --> 00:07:54,535 had similar to higher 200 00:07:54,995 --> 00:07:56,694 FEC and DLCO values. 201 00:07:57,555 --> 00:07:59,394 That's really helpful context. I mean, I feel 202 00:07:59,394 --> 00:08:01,634 like fits with what I'm admittedly in my 203 00:08:01,634 --> 00:08:03,254 relatively short time as a pulmonologist. 204 00:08:03,634 --> 00:08:05,850 In my experience, I feel like people get 205 00:08:05,850 --> 00:08:07,610 so many more CAT scans than it feels 206 00:08:07,610 --> 00:08:09,850 like they did even five years ago now. 207 00:08:09,850 --> 00:08:12,270 And I imagine we're just catching folks 208 00:08:12,730 --> 00:08:13,709 a little bit earlier 209 00:08:14,009 --> 00:08:15,290 for a, they get a CT of their 210 00:08:15,290 --> 00:08:17,050 belly and there's something at the base now, 211 00:08:17,050 --> 00:08:17,550 or 212 00:08:18,044 --> 00:08:20,444 nodules for lung cancer screening and we find 213 00:08:20,444 --> 00:08:21,745 some interstitial abnormality. 214 00:08:22,444 --> 00:08:24,604 Absolutely. I think that's definitely true that we're 215 00:08:24,604 --> 00:08:27,164 seeing more incidental diagnoses of ILDs, and then 216 00:08:27,164 --> 00:08:28,925 that's why we have this huge area of 217 00:08:28,925 --> 00:08:32,044 interstitial lung abnormalities that is also being intact 218 00:08:32,044 --> 00:08:32,625 as well. 219 00:08:33,070 --> 00:08:34,750 Yeah, for sure. If the ILAs that I 220 00:08:34,750 --> 00:08:36,509 still have not graduated yet, so I have 221 00:08:36,509 --> 00:08:37,950 time still to learn what to do with 222 00:08:37,950 --> 00:08:40,450 them, but. So we're all still learning. Yeah. 223 00:08:41,549 --> 00:08:43,070 All right. So Robert, do you mind telling 224 00:08:43,070 --> 00:08:44,190 us a little bit, what did they do? 225 00:08:44,190 --> 00:08:45,169 What was the intervention? 226 00:08:45,975 --> 00:08:48,054 Yeah. This was pretty straightforward. So they had 227 00:08:48,054 --> 00:08:50,855 about 1,200 patients, and they randomized them one 228 00:08:50,855 --> 00:08:53,495 to one to urine on the last eighteen 229 00:08:53,495 --> 00:08:54,714 milligrams BID 230 00:08:55,095 --> 00:08:57,975 or nine milligrams or placebo. They stratify the 231 00:08:57,975 --> 00:08:58,475 randomization 232 00:08:58,855 --> 00:09:01,355 according to background and fibrotic use. 233 00:09:01,870 --> 00:09:03,550 First of all, before going into the actual 234 00:09:03,550 --> 00:09:05,629 results, we should always look at the CONSORT 235 00:09:05,629 --> 00:09:08,029 diagram to help us understand how patients flow 236 00:09:08,029 --> 00:09:08,850 through this study. 237 00:09:09,230 --> 00:09:11,470 There were discontinuations in all the trial groups, 238 00:09:11,470 --> 00:09:13,950 so about seventy out of three ninety in 239 00:09:13,950 --> 00:09:15,870 each group. Most completed the fifty two week 240 00:09:15,870 --> 00:09:17,009 incarceration period. 241 00:09:18,115 --> 00:09:19,954 And upstream of that, a pretty good proportion 242 00:09:19,954 --> 00:09:22,034 of patients who were assessed were randomized, which 243 00:09:22,034 --> 00:09:23,954 is reassuring that the study team wasn't cherry 244 00:09:23,954 --> 00:09:26,294 picking patients that they thought would benefit. 245 00:09:26,995 --> 00:09:29,014 And so for the primary outcome, 246 00:09:29,409 --> 00:09:31,590 there was about a 60 to 70 milliliter 247 00:09:31,649 --> 00:09:35,250 difference in FVC between the placebo group and 248 00:09:35,250 --> 00:09:37,269 most of the higher and lower dose groups, 249 00:09:37,330 --> 00:09:38,230 which was significant 250 00:09:38,529 --> 00:09:40,710 at a alpha of 0.05. 251 00:09:40,769 --> 00:09:42,929 This is a pretty similar effect size to 252 00:09:42,929 --> 00:09:46,074 the phase two, except that the baseline decline 253 00:09:46,074 --> 00:09:48,735 in FVC was higher such that nerondamilast 254 00:09:49,194 --> 00:09:51,995 didn't halt FVC decline as we thought it 255 00:09:51,995 --> 00:09:53,774 might based on a phase two trial. 256 00:09:54,315 --> 00:09:56,634 Some other notes about the results is a 257 00:09:56,634 --> 00:09:58,799 drug interaction with profenadone 258 00:09:59,660 --> 00:10:00,399 and neurodomelast, 259 00:10:01,100 --> 00:10:01,840 such that 260 00:10:02,220 --> 00:10:05,040 the patients who were receiving background profenadone 261 00:10:05,500 --> 00:10:08,160 via the eighteen milligram dose to be effective. 262 00:10:09,259 --> 00:10:11,259 Thank you for walking us through that. The 263 00:10:11,259 --> 00:10:13,440 drug interaction portion is really interesting. 264 00:10:13,835 --> 00:10:15,195 I know Doctor. Ng, when we were talking 265 00:10:15,195 --> 00:10:16,715 about this paper earlier, this was a thing 266 00:10:16,715 --> 00:10:19,195 that you had some thoughts about and in 267 00:10:19,195 --> 00:10:22,075 particular, their figure two, which folks listening at 268 00:10:22,075 --> 00:10:23,914 home alone can take a look at this 269 00:10:23,914 --> 00:10:26,075 to follow along with us. But would you 270 00:10:26,075 --> 00:10:28,335 mind sharing your thoughts on how 271 00:10:28,910 --> 00:10:31,170 this drug ever seemed to interact with profenadone 272 00:10:31,389 --> 00:10:33,009 and so with the dosing of nirandomolast? 273 00:10:34,029 --> 00:10:36,110 So I think it's very interesting. So when 274 00:10:36,110 --> 00:10:38,110 I first looked at figure two, it looks 275 00:10:38,110 --> 00:10:40,210 like there's a clean dose dependent relationship 276 00:10:40,764 --> 00:10:41,745 such that the Neurandemlast 277 00:10:42,125 --> 00:10:45,324 eighteen milligram had the lowest change in the 278 00:10:45,324 --> 00:10:47,964 FEC followed by the nine milligram and then 279 00:10:47,964 --> 00:10:48,625 the placebo. 280 00:10:49,804 --> 00:10:52,144 But I think that this relationship 281 00:10:52,700 --> 00:10:55,500 is driven primarily by the effects of the 282 00:10:55,500 --> 00:10:56,960 interaction between pirfenidone 283 00:10:57,339 --> 00:11:00,299 and the nine milligram of nerandomolast because of 284 00:11:00,299 --> 00:11:02,320 that interaction rendering it ineffective 285 00:11:02,779 --> 00:11:03,600 and, therefore, 286 00:11:05,644 --> 00:11:08,285 attenuating the effects of the nine milligram dose 287 00:11:08,285 --> 00:11:10,925 because the nine and eighteen milligram dose appears 288 00:11:10,925 --> 00:11:12,925 to be pretty similar. If you look at 289 00:11:12,925 --> 00:11:14,304 the other groups of patients, 290 00:11:14,605 --> 00:11:17,345 such as the patients not taking background antithyrotic 291 00:11:17,644 --> 00:11:18,144 therapy 292 00:11:18,600 --> 00:11:21,480 and those taking background entendib. So, you know, 293 00:11:21,480 --> 00:11:22,620 patients on emprazenadone, 294 00:11:23,079 --> 00:11:25,320 the differences between the nine and eighteen milligram 295 00:11:25,320 --> 00:11:25,820 doses, 296 00:11:26,919 --> 00:11:28,839 there, there was no difference between those two 297 00:11:28,839 --> 00:11:29,339 groups. 298 00:11:29,879 --> 00:11:32,120 Yeah. That is really interesting. And to your 299 00:11:32,120 --> 00:11:33,659 point here too, at 300 00:11:34,085 --> 00:11:36,004 at first glance, I don't think I initially 301 00:11:36,004 --> 00:11:37,605 appreciated why they had reported this, but now 302 00:11:37,605 --> 00:11:39,285 that we've talked to it and more, I'm 303 00:11:39,285 --> 00:11:42,024 glad they did. The authors actually measured plasma 304 00:11:42,164 --> 00:11:43,465 trough levels of neuroendomolast 305 00:11:44,085 --> 00:11:45,945 at steady state and folks who 306 00:11:46,370 --> 00:11:49,250 had about a 50% lower level than others. 307 00:11:49,250 --> 00:11:50,929 And it's a point well taken. I think 308 00:11:50,929 --> 00:11:53,490 the eighteen milligram dose seems what I have 309 00:11:53,490 --> 00:11:55,649 seen folks using, but it does make me 310 00:11:55,649 --> 00:11:58,549 wonder whether the nine milligram dose works too. 311 00:11:59,009 --> 00:12:00,794 All right. And so Robert, would you mind 312 00:12:00,794 --> 00:12:02,315 telling us, we talked a little bit about 313 00:12:02,315 --> 00:12:03,835 the primary outcome, but I know they looked 314 00:12:03,835 --> 00:12:05,995 at some other things too. Can you walk 315 00:12:05,995 --> 00:12:08,335 us through some of their secondary outcomes here? 316 00:12:09,355 --> 00:12:11,355 Yeah. And this is important because their P 317 00:12:11,355 --> 00:12:13,754 secondary endpoint again, was this tied to event 318 00:12:13,754 --> 00:12:15,695 analysis of first acute exacerbation, 319 00:12:16,449 --> 00:12:19,409 hospitalization for respiratory cause or death, and there 320 00:12:19,409 --> 00:12:22,370 was really no benefit seen. No no harm 321 00:12:22,370 --> 00:12:25,250 seen, but no benefit seen to neuroendal to 322 00:12:25,250 --> 00:12:27,490 last, which was fairly disappointing. This was a 323 00:12:27,490 --> 00:12:29,029 more patient centered endpoint. 324 00:12:29,334 --> 00:12:31,014 And there are really no improvements in any 325 00:12:31,014 --> 00:12:32,934 of its components or in the proportion of 326 00:12:32,934 --> 00:12:34,394 patients with a large decline 327 00:12:34,855 --> 00:12:36,475 in FBC or DLCO. 328 00:12:37,174 --> 00:12:38,934 And I'll kick it back to the two 329 00:12:38,934 --> 00:12:41,014 of you. I have my thoughts, but why 330 00:12:41,014 --> 00:12:42,774 do you think it might be that we 331 00:12:42,774 --> 00:12:44,610 didn't see any improvement 332 00:12:45,950 --> 00:12:48,590 here? Yeah. So these secondary endpoints are not 333 00:12:48,590 --> 00:12:50,509 common. And so that's why the composite was 334 00:12:50,509 --> 00:12:52,690 used. I mean, we need large sample sizes 335 00:12:52,750 --> 00:12:55,309 on long durations of follow-up to detect such 336 00:12:55,309 --> 00:12:56,610 a difference if present. 337 00:12:57,204 --> 00:12:59,044 A limitation to the study was that these 338 00:12:59,044 --> 00:13:00,904 events were not centrally adjudicated. 339 00:13:01,605 --> 00:13:04,245 There was no difference found in the composite 340 00:13:04,245 --> 00:13:06,404 or in the event individual events in the 341 00:13:06,404 --> 00:13:09,059 IPF trial. But in the fibrony or ILD 342 00:13:09,059 --> 00:13:11,480 trial, there was a trend favoring the randomized 343 00:13:11,779 --> 00:13:14,980 and the same key secondary endpoints, particularly with 344 00:13:14,980 --> 00:13:15,480 mortality. 345 00:13:16,100 --> 00:13:19,159 And more recently, pooled analyses of the fibroneer 346 00:13:19,460 --> 00:13:23,004 IPF with the fibroneer ILD trials did show 347 00:13:23,004 --> 00:13:25,804 anomaly significant reduction in the risk of death 348 00:13:25,804 --> 00:13:29,184 by fifty nine percent in those on Neurandum 349 00:13:29,245 --> 00:13:31,584 last eighteen milligrams versus placebo. 350 00:13:32,445 --> 00:13:34,284 So it sounds like you're an optimist. Do 351 00:13:34,284 --> 00:13:35,804 you think that if we extended this out, 352 00:13:35,804 --> 00:13:37,184 if we had all the patients, 353 00:13:37,490 --> 00:13:40,610 we would show some more significant patient centered 354 00:13:40,610 --> 00:13:41,110 endpoints? 355 00:13:41,649 --> 00:13:43,970 And I think so. And it also makes 356 00:13:43,970 --> 00:13:44,789 me think of, 357 00:13:45,409 --> 00:13:49,009 by corollary to the our earlier discussion about 358 00:13:49,009 --> 00:13:51,809 impulses where they have this pooled analysis showing 359 00:13:51,809 --> 00:13:55,154 your reduction in acute exacerbations when you have 360 00:13:55,154 --> 00:13:57,714 enough data. I think that's the optimistic reading 361 00:13:57,714 --> 00:13:59,634 and then the pessimistic reading would be that 362 00:13:59,634 --> 00:14:02,455 it truly doesn't affect anything other than FEC. 363 00:14:03,714 --> 00:14:06,274 Yeah. I am cautiously optimistic that as we 364 00:14:06,274 --> 00:14:08,529 go forward and we get more experience and 365 00:14:08,529 --> 00:14:11,090 data with this agent that hopefully we'll see 366 00:14:11,090 --> 00:14:12,930 some signals towards benefit in some of these 367 00:14:12,930 --> 00:14:14,149 things as well. I think 368 00:14:14,529 --> 00:14:17,250 FEC decline is important, but it's a space 369 00:14:17,250 --> 00:14:18,850 where I think getting a win and one 370 00:14:18,850 --> 00:14:20,629 of those other things would be pretty meaningful. 371 00:14:21,264 --> 00:14:22,705 All right. And so we've talked a little 372 00:14:22,705 --> 00:14:24,705 bit about kind of the efficacy of the 373 00:14:24,705 --> 00:14:27,044 drug, but I think it's also helpful, especially 374 00:14:27,424 --> 00:14:29,924 on the topic of anti fibrotics that notoriously 375 00:14:30,065 --> 00:14:31,044 have side effects. 376 00:14:31,424 --> 00:14:33,524 Thinking about the adverse events here, 377 00:14:33,825 --> 00:14:36,004 Robert, how did folks tolerate this? 378 00:14:36,879 --> 00:14:39,199 We expected side effects in this trial, and 379 00:14:39,199 --> 00:14:40,959 they were common in all the groups, including 380 00:14:40,959 --> 00:14:44,419 the placebo group, but there weren't any more 381 00:14:44,639 --> 00:14:47,360 serious adverse events or fatal events or things 382 00:14:47,360 --> 00:14:49,379 that led to interruption of the trial regimen 383 00:14:49,440 --> 00:14:50,740 in the treated groups. 384 00:14:51,105 --> 00:14:53,044 The most common side effect is diarrhea, 385 00:14:53,424 --> 00:14:55,985 occurred in forty one percent of the overall 386 00:14:55,985 --> 00:14:57,584 high dose group. And then in the folks 387 00:14:57,584 --> 00:14:59,745 who were also taking intetinib, it was as 388 00:14:59,745 --> 00:15:01,205 high as sixty two percent, 389 00:15:01,745 --> 00:15:02,565 which seems 390 00:15:03,120 --> 00:15:05,440 unsurprising to me. Doctor. Hain, did you have 391 00:15:05,440 --> 00:15:07,519 anything else to add about the side effect 392 00:15:07,519 --> 00:15:08,019 profile? 393 00:15:08,720 --> 00:15:11,440 Yeah. Yes. So I would add that most 394 00:15:11,440 --> 00:15:12,419 of these cases 395 00:15:12,799 --> 00:15:14,899 were of mild diarrhea that was manageable. 396 00:15:15,464 --> 00:15:16,204 So expectedly 397 00:15:16,584 --> 00:15:17,404 with nirandamilast, 398 00:15:18,024 --> 00:15:20,345 those taking background and entendinib, they had the 399 00:15:20,345 --> 00:15:23,164 highest rate of diarrhea in sixty two percent. 400 00:15:23,384 --> 00:15:26,264 Otherwise, about a quarter of patients developed diarrhea, 401 00:15:26,264 --> 00:15:29,245 whether they are on background profenidone or nothing. 402 00:15:29,549 --> 00:15:32,029 The higher dose of the eighteen milligram did 403 00:15:32,029 --> 00:15:34,830 lead to more diarrhea with twenty six percent 404 00:15:34,830 --> 00:15:37,570 versus seventeen percent without background therapy. 405 00:15:38,429 --> 00:15:40,509 But I would highlight most of these cases 406 00:15:40,509 --> 00:15:43,250 were mild. In patients who were taking nintenib, 407 00:15:43,904 --> 00:15:45,985 thirteen percent of those on the high dose 408 00:15:45,985 --> 00:15:47,745 and two percent of those on the low 409 00:15:47,745 --> 00:15:50,384 dose had to discontinue treatment because of the 410 00:15:50,384 --> 00:15:53,105 diarrhea, and only one percent of patients needed 411 00:15:53,105 --> 00:15:55,584 to discontinue that on their random last 18 412 00:15:55,584 --> 00:15:56,084 alone. 413 00:15:56,459 --> 00:15:58,860 So in summary, much less diarrhea compared to 414 00:15:58,860 --> 00:15:59,759 prior antibiotics, 415 00:16:00,299 --> 00:16:01,439 especially in Atenib. 416 00:16:01,740 --> 00:16:04,240 And when present, tends to be mild, manageable, 417 00:16:04,299 --> 00:16:07,039 and not necessitating discontinuation of therapy. 418 00:16:07,579 --> 00:16:10,714 Modifying two factors are dose of nerandom last 419 00:16:10,714 --> 00:16:11,695 as well as concomitant 420 00:16:12,714 --> 00:16:13,214 antifibrotic 421 00:16:13,514 --> 00:16:14,575 use, but overall, 422 00:16:15,115 --> 00:16:16,254 fairly well tolerated. 423 00:16:17,754 --> 00:16:19,995 Yeah. That's good to hear. I think one 424 00:16:19,995 --> 00:16:22,460 other nice safety signal to call out here, 425 00:16:22,460 --> 00:16:23,740 just given that it was part of those 426 00:16:23,740 --> 00:16:26,860 exclusion criteria we mentioned, and theoretically, could it 427 00:16:26,860 --> 00:16:28,480 be a risk, I should say, of neuroendomolast 428 00:16:28,779 --> 00:16:31,259 and not the other anti fibroducts is there 429 00:16:31,259 --> 00:16:32,940 was actually no difference in the rates of 430 00:16:32,940 --> 00:16:33,440 vasculitis, 431 00:16:34,024 --> 00:16:35,485 depression, and or suicidality 432 00:16:35,945 --> 00:16:37,644 between any of the groups either. 433 00:16:38,504 --> 00:16:41,225 And agree the adverse events of special interests 434 00:16:41,225 --> 00:16:43,725 were not more common in the treatment arms. 435 00:16:44,745 --> 00:16:46,745 And so, Robert, we've talked a little bit 436 00:16:46,745 --> 00:16:47,965 about safety and efficacy. 437 00:16:48,350 --> 00:16:50,190 Can you speak to any of the quality 438 00:16:50,190 --> 00:16:52,029 of life outcomes for folks? Cause I know 439 00:16:52,029 --> 00:16:53,870 that's also been a sticking point with some 440 00:16:53,870 --> 00:16:55,649 of our anti fibrotics as well. 441 00:16:56,590 --> 00:16:59,629 For sure. Here, the results for health related 442 00:16:59,629 --> 00:17:00,929 quality of life were 443 00:17:01,365 --> 00:17:04,164 truly neutral, that not in any subgroup. Was 444 00:17:04,164 --> 00:17:06,404 there any significant difference? And the other thing 445 00:17:06,404 --> 00:17:09,444 that was disappointing was that it declined across 446 00:17:09,444 --> 00:17:11,464 every metric in every single subgroup, 447 00:17:11,924 --> 00:17:14,644 just reflecting how serious of a disease that 448 00:17:14,644 --> 00:17:16,345 this is, and we need better therapies. 449 00:17:17,140 --> 00:17:20,099 So unless we have a disease modifying treatment 450 00:17:20,099 --> 00:17:22,019 that is able to reverse or improve the 451 00:17:22,019 --> 00:17:25,460 underlying scarring, patients will continue to progress. And 452 00:17:25,460 --> 00:17:28,660 unfortunately we won't see meaningful improvements in health 453 00:17:28,660 --> 00:17:31,700 related quality of life parameters because they aren't 454 00:17:31,700 --> 00:17:32,519 getting better. 455 00:17:33,974 --> 00:17:36,295 Yeah. And I would argue that's reflected here. 456 00:17:36,295 --> 00:17:38,934 It did slow progression, but people still did 457 00:17:38,934 --> 00:17:40,855 progress. And like we've mentioned, none of those 458 00:17:40,855 --> 00:17:43,914 measures of quality of life improved, which is 459 00:17:44,455 --> 00:17:46,455 a victory still. And that it's an effective 460 00:17:46,455 --> 00:17:48,450 tool, not as, as maybe as robust, 461 00:17:49,089 --> 00:17:51,569 an outcome as we maybe hoped for based 462 00:17:51,569 --> 00:17:53,589 on some of the earlier, like phase two 463 00:17:53,650 --> 00:17:54,150 trials. 464 00:17:54,769 --> 00:17:56,289 And so Robert, we've talked a little bit 465 00:17:56,289 --> 00:17:57,970 about the nitty gritty. I'm curious, taking a 466 00:17:57,970 --> 00:18:00,289 step back, how you think about this paper 467 00:18:00,289 --> 00:18:01,509 and the results overall. 468 00:18:02,474 --> 00:18:03,615 So just to summarize, 469 00:18:03,994 --> 00:18:06,555 we have a decrease in the magnitude of 470 00:18:06,555 --> 00:18:07,615 FVC decline 471 00:18:08,075 --> 00:18:09,994 without any evidence of benefit in any other 472 00:18:09,994 --> 00:18:13,835 meaningful outcome, including mortality, exacerbations, health related quality 473 00:18:13,835 --> 00:18:14,494 of life. 474 00:18:14,960 --> 00:18:17,519 So then we have to wrestle with how 475 00:18:17,519 --> 00:18:20,240 much does this FVC decline matter. To put 476 00:18:20,240 --> 00:18:22,240 this effect size into context, this is about 477 00:18:22,240 --> 00:18:24,640 half the reduction in FVC decline seen within 478 00:18:24,640 --> 00:18:26,319 10 and m, so up to 65 mils 479 00:18:26,319 --> 00:18:27,059 per year. 480 00:18:27,519 --> 00:18:28,019 And 481 00:18:28,945 --> 00:18:30,164 some of the benchmarks 482 00:18:30,465 --> 00:18:33,184 that that I read about were that five 483 00:18:33,184 --> 00:18:35,424 to 10% decline in absolute FPC over a 484 00:18:35,424 --> 00:18:37,744 year is associated with a hazard ratio of 485 00:18:37,744 --> 00:18:39,525 one point three four mortality, 486 00:18:40,305 --> 00:18:42,945 and a decline of more than 15% carries 487 00:18:42,945 --> 00:18:45,000 a much greater hazard ratio of zero point 488 00:18:45,000 --> 00:18:45,500 one. 489 00:18:45,799 --> 00:18:47,420 So we are hoping that 490 00:18:48,039 --> 00:18:48,539 the 491 00:18:48,920 --> 00:18:51,960 reduction in FEC decline will eventually translate to 492 00:18:51,960 --> 00:18:54,519 a patient important outcome. And I'll turn it 493 00:18:54,519 --> 00:18:55,720 over to you all. I mean, do you 494 00:18:55,720 --> 00:18:57,480 guys think that is worth it? Is that 495 00:18:57,480 --> 00:18:58,779 something we should be pursuing 496 00:18:59,080 --> 00:18:59,740 right now? 497 00:19:01,505 --> 00:19:03,424 Yeah. So I think it is. I might 498 00:19:03,424 --> 00:19:05,105 be biased, but I think it is. I 499 00:19:05,105 --> 00:19:07,605 think the effect size still is clinically meaningful, 500 00:19:07,664 --> 00:19:10,164 especially as we know that patients with IPF 501 00:19:10,304 --> 00:19:12,865 despite treatment still progress. So anything we do 502 00:19:12,865 --> 00:19:15,345 that can further slow down to disease progression 503 00:19:15,345 --> 00:19:16,005 is meaningful. 504 00:19:16,519 --> 00:19:18,679 And while it's tempting, it would be inaccurate 505 00:19:18,679 --> 00:19:21,899 to compare the absolute differences in the FEC 506 00:19:21,960 --> 00:19:24,119 whether with Ascend. You can say that was 507 00:19:24,119 --> 00:19:27,079 roughly 200 cc's versus in Pulsus, roughly a 508 00:19:27,079 --> 00:19:27,880 110 509 00:19:27,880 --> 00:19:29,019 compared to fibroneer. 510 00:19:30,174 --> 00:19:32,275 Even in the ASCEND and I in Pulsus 511 00:19:32,414 --> 00:19:35,055 IPF studies that occurred within the same time 512 00:19:35,055 --> 00:19:38,015 frame, the patient populations were quite different. The 513 00:19:38,015 --> 00:19:40,734 baseline characteristics of patients in the ASCEND trial 514 00:19:40,734 --> 00:19:43,375 did have lower FPC and DLCLs than that 515 00:19:43,375 --> 00:19:44,195 of in Pulsus. 516 00:19:45,269 --> 00:19:46,789 So I I actually like to look at 517 00:19:46,789 --> 00:19:48,869 the placebo groups and trials because it gives 518 00:19:48,869 --> 00:19:50,630 you a look at the natural history of 519 00:19:50,630 --> 00:19:53,750 the disease course and how patients recruited into 520 00:19:53,750 --> 00:19:55,509 the study at that time were doing without 521 00:19:55,509 --> 00:19:56,009 intervention. 522 00:19:56,644 --> 00:19:59,044 The FEC decline in the placebo groups were 523 00:19:59,044 --> 00:20:00,984 about 400 cc's in ASCEND, 524 00:20:01,365 --> 00:20:02,484 two to 240 525 00:20:02,484 --> 00:20:04,244 cc's in a pulse is one to c 526 00:20:04,404 --> 00:20:06,964 one to two, and a 150 cc's in 527 00:20:06,964 --> 00:20:09,384 fibroneer, which has the lowest rate of decline. 528 00:20:09,619 --> 00:20:12,340 So perhaps patients in the FibroNIR trial were 529 00:20:12,340 --> 00:20:14,259 less sick as we mentioned before because of 530 00:20:14,259 --> 00:20:16,740 the differences in the PFT parameters and rate 531 00:20:16,740 --> 00:20:17,880 of FEC decline. 532 00:20:18,259 --> 00:20:19,400 So I'd attribute 533 00:20:19,700 --> 00:20:21,000 these improvements 534 00:20:21,715 --> 00:20:24,355 to, like we said earlier, diagnosis lead time 535 00:20:24,355 --> 00:20:26,674 bias, but also improvements in standard of care 536 00:20:26,674 --> 00:20:27,735 that we have antibiotics 537 00:20:28,115 --> 00:20:30,934 referral to palm rehab, use of supplemental oxygen 538 00:20:31,075 --> 00:20:32,215 management of comorbidities, 539 00:20:32,595 --> 00:20:33,095 etcetera. 540 00:20:34,230 --> 00:20:36,230 Yeah, that is a really helpful context. And 541 00:20:36,230 --> 00:20:37,589 I do think, I mean, to me, this 542 00:20:37,589 --> 00:20:40,410 is, these are still compelling results. So I 543 00:20:40,470 --> 00:20:42,390 think it seems in my mind to fit 544 00:20:42,390 --> 00:20:44,230 kind of a piece with the other NITFI 545 00:20:44,230 --> 00:20:44,730 products. 546 00:20:45,029 --> 00:20:47,349 I am curious. I know we can't quite 547 00:20:47,349 --> 00:20:49,424 compare them head to head, but I am 548 00:20:49,424 --> 00:20:51,744 curious, doctoring, how in your mind, how this 549 00:20:51,744 --> 00:20:53,424 kind of fits in context with some of 550 00:20:53,424 --> 00:20:56,144 the other trials, whether for the other agents, 551 00:20:56,144 --> 00:20:56,964 I should say. 552 00:20:57,904 --> 00:21:00,304 Absolutely. And this is the question everyone's asking. 553 00:21:00,304 --> 00:21:01,585 And it's sort of a head to head 554 00:21:01,585 --> 00:21:02,085 trial. 555 00:21:02,809 --> 00:21:04,569 We would have to consider these to be 556 00:21:04,569 --> 00:21:06,730 relatively similar, and we can't say which if 557 00:21:06,730 --> 00:21:08,269 one is better than the other. 558 00:21:08,970 --> 00:21:10,890 I would say within each of these trials, 559 00:21:10,890 --> 00:21:11,549 the intervention 560 00:21:11,849 --> 00:21:14,190 did lead to a relative reduction 561 00:21:14,730 --> 00:21:16,809 in FBC. This is hand waving maybe around 562 00:21:16,809 --> 00:21:17,609 50%. 563 00:21:17,609 --> 00:21:20,105 If you consider the numbers in a SEN, 564 00:21:20,105 --> 00:21:22,424 the the difference is 235 565 00:21:22,424 --> 00:21:24,904 versus four twenty eight, and pulse is a 566 00:21:24,904 --> 00:21:27,865 110 versus 200 to two forty ccs, and 567 00:21:27,865 --> 00:21:30,825 fibrinear 70 versus a 150 ccs if you're 568 00:21:30,825 --> 00:21:33,900 looking at the no background therapy group. One 569 00:21:33,900 --> 00:21:35,900 additional point I wanted to bring up about 570 00:21:35,900 --> 00:21:37,500 figure two is that if you focus on 571 00:21:37,500 --> 00:21:40,140 these placebo groups once again, the change in 572 00:21:40,140 --> 00:21:42,940 FEC in the overall population was a 180 573 00:21:42,940 --> 00:21:43,440 cc's. 574 00:21:43,820 --> 00:21:45,920 So when you stratify it based on 575 00:21:46,700 --> 00:21:47,840 background of antifibrotic, 576 00:21:48,955 --> 00:21:51,615 the decline was lowest in those taking nintenib 577 00:21:51,755 --> 00:21:52,414 or profenidone 578 00:21:52,715 --> 00:21:55,835 at a 190 cc's compared to those non 579 00:21:55,835 --> 00:21:58,235 on anti fibrotic therapy at a 150 580 00:21:58,235 --> 00:22:00,634 cc's. In other words, at first glance, it 581 00:22:00,634 --> 00:22:03,035 almost looks like patients who are taking anti 582 00:22:03,035 --> 00:22:03,535 fibrotics 583 00:22:04,009 --> 00:22:06,490 had a greater decline in FVC than those 584 00:22:06,490 --> 00:22:07,470 not on therapy. 585 00:22:08,009 --> 00:22:09,369 At first, it didn't make sense. I was 586 00:22:09,369 --> 00:22:12,809 also considering the fibroneer ILD trial where the 587 00:22:12,809 --> 00:22:15,230 same trend happened on background entetinib. 588 00:22:16,024 --> 00:22:18,424 It was a drop of 180 cc's versus 589 00:22:18,424 --> 00:22:21,464 one fifty without background therapy. But here, it 590 00:22:21,464 --> 00:22:23,884 made more sense because patients in the fibroneer 591 00:22:24,024 --> 00:22:25,404 ILD trial, they had 592 00:22:25,944 --> 00:22:29,304 progressive pulmonary fibroids system. They were selectively chosen 593 00:22:29,304 --> 00:22:30,284 to have progression 594 00:22:30,789 --> 00:22:33,450 based on FEC and or imaging and symptoms 595 00:22:33,750 --> 00:22:34,890 despite antifibrotics. 596 00:22:35,910 --> 00:22:36,650 But here, 597 00:22:37,029 --> 00:22:39,130 in the fibroneer IPF trials, 598 00:22:39,509 --> 00:22:41,690 documented progression is not a requisite. 599 00:22:42,549 --> 00:22:44,650 But ultimately, I do think patients 600 00:22:45,265 --> 00:22:46,005 on antifibrotics 601 00:22:46,464 --> 00:22:49,025 in both studies were more likely to have 602 00:22:49,025 --> 00:22:51,984 advanced the disease than those not on background 603 00:22:51,984 --> 00:22:54,065 treatment, what we call channeling bias. I think 604 00:22:54,065 --> 00:22:56,404 this is supported by data in the supplementary 605 00:22:57,184 --> 00:23:00,480 appendix table f three, which is suggestive that 606 00:23:00,480 --> 00:23:02,100 patients on background antifibrotic 607 00:23:02,640 --> 00:23:03,380 were likely 608 00:23:04,080 --> 00:23:06,580 thicker with a longer time since diagnosis, 609 00:23:06,960 --> 00:23:10,259 lower PFT parameters, and increased use of supplemental 610 00:23:10,480 --> 00:23:10,980 oxygen. 611 00:23:12,304 --> 00:23:14,164 I'm not sure that the differences 612 00:23:14,704 --> 00:23:17,265 are significant enough to yield the differences in 613 00:23:17,265 --> 00:23:19,505 the FEC outcomes we saw, but I think 614 00:23:19,505 --> 00:23:22,164 it does indicate that channeling bias is likely 615 00:23:22,224 --> 00:23:23,045 playing a role. 616 00:23:23,984 --> 00:23:26,269 Yeah, that makes sense to me. I think 617 00:23:26,269 --> 00:23:27,869 it was, I was also a little like 618 00:23:27,869 --> 00:23:30,269 taken aback that at first glance, it seemed 619 00:23:30,269 --> 00:23:32,349 like the folks who were on therapy did 620 00:23:32,349 --> 00:23:34,349 worse than folks on placebo, but it, I 621 00:23:34,349 --> 00:23:37,404 think the way you've framed it, I could 622 00:23:37,404 --> 00:23:40,285 find pretty convincing, that it's more that the 623 00:23:40,285 --> 00:23:42,684 people who were already doing worse or had 624 00:23:42,684 --> 00:23:44,204 more advanced disease are the ones who are 625 00:23:44,204 --> 00:23:45,984 gonna come into this trial and therapy, 626 00:23:46,365 --> 00:23:48,845 especially since they weren't being selected where everybody 627 00:23:48,845 --> 00:23:49,585 was progressive 628 00:23:49,970 --> 00:23:51,570 as a requirement to be enrolled in the 629 00:23:51,570 --> 00:23:52,930 first place. That makes a lot of sense 630 00:23:52,930 --> 00:23:53,509 to me. 631 00:23:54,130 --> 00:23:56,049 I think those are really important points. And 632 00:23:56,049 --> 00:23:56,869 I guess that 633 00:23:57,329 --> 00:23:59,170 begs the question of where does that leave 634 00:23:59,170 --> 00:24:00,769 us now? What are the gaps in the 635 00:24:00,769 --> 00:24:03,269 field? And, specifically, I was wondering 636 00:24:03,809 --> 00:24:05,009 what you might think about 637 00:24:05,615 --> 00:24:07,375 or how you might think about first line 638 00:24:07,375 --> 00:24:07,875 therapy 639 00:24:08,174 --> 00:24:10,755 in people who are being considered for neuroendomelast 640 00:24:11,215 --> 00:24:14,414 because the trial itself doesn't necessarily stipulate that 641 00:24:14,414 --> 00:24:17,474 you have to start someone on another antifibrotic 642 00:24:17,695 --> 00:24:19,715 first, or should we be starting neuroendomelast 643 00:24:20,095 --> 00:24:20,595 first? 644 00:24:20,940 --> 00:24:22,880 How are you thinking about that, Doctor. Ng? 645 00:24:23,579 --> 00:24:25,200 I'm still thinking about it. 646 00:24:26,139 --> 00:24:26,639 Awesome. 647 00:24:26,940 --> 00:24:28,539 Short of head to head trials, we can't 648 00:24:28,539 --> 00:24:31,019 say which medication is more effective. In IPF, 649 00:24:31,019 --> 00:24:32,480 I would say all three antifibrotics 650 00:24:32,859 --> 00:24:33,919 are fair game. 651 00:24:34,845 --> 00:24:37,345 My approach would be a shared decision making 652 00:24:37,565 --> 00:24:38,865 process with patients. 653 00:24:39,244 --> 00:24:41,265 I probably favor Neurandemlast 654 00:24:41,724 --> 00:24:42,224 more 655 00:24:42,605 --> 00:24:44,924 for several reasons. One thing we haven't discussed 656 00:24:44,924 --> 00:24:46,619 is that we don't need to do labs. 657 00:24:46,779 --> 00:24:48,119 This is huge. 658 00:24:48,460 --> 00:24:51,019 For patients, for providers, we don't have to 659 00:24:51,019 --> 00:24:52,779 bring them back after a couple of weeks 660 00:24:52,779 --> 00:24:54,880 and then do labs every three months. 661 00:24:55,579 --> 00:24:57,680 And so I think that's a huge win 662 00:24:57,900 --> 00:25:01,325 for norandom last. Secondly, GI side effects are 663 00:25:01,325 --> 00:25:01,825 significantly 664 00:25:02,525 --> 00:25:05,265 better with nerandom last than with mentenad. 665 00:25:06,525 --> 00:25:09,265 Other considerations in terms of use, so prophenidone 666 00:25:09,404 --> 00:25:11,005 is used three times a day. Some of 667 00:25:11,005 --> 00:25:13,005 my patients really don't like doing that. And 668 00:25:13,005 --> 00:25:14,980 so all of these little things matter. And 669 00:25:14,980 --> 00:25:17,460 so typically I would have this discussion with 670 00:25:17,460 --> 00:25:19,400 the patients. And I think this also leads 671 00:25:20,259 --> 00:25:21,940 us to the next question of what is 672 00:25:21,940 --> 00:25:23,240 our approach to 673 00:25:24,660 --> 00:25:26,039 managing these patients 674 00:25:26,455 --> 00:25:29,335 if they're taking background therapy or if they're 675 00:25:29,335 --> 00:25:31,894 not taking background therapy. Would you do upfront 676 00:25:31,894 --> 00:25:33,975 combination therapy or would you do add on 677 00:25:33,975 --> 00:25:34,475 therapy? 678 00:25:35,015 --> 00:25:37,755 So I generally favor add on therapy because 679 00:25:37,815 --> 00:25:39,654 when a patient has side effects, you don't 680 00:25:39,654 --> 00:25:41,174 know which one it's from, and you just 681 00:25:41,174 --> 00:25:42,450 have to take a guess as to which 682 00:25:42,450 --> 00:25:44,763 one you'll peel back on. But it does 683 00:25:44,763 --> 00:25:47,250 slow down the process to get patients on 684 00:25:47,250 --> 00:25:48,789 maximal medical therapy. 685 00:25:49,169 --> 00:25:51,409 So I think similarly in this space too, 686 00:25:51,409 --> 00:25:53,829 I also have a shared decision making process 687 00:25:54,130 --> 00:25:56,774 and discuss the options to patients for a 688 00:25:56,774 --> 00:25:57,674 single antifibrotic 689 00:25:58,134 --> 00:25:59,034 versus combination 690 00:25:59,335 --> 00:25:59,835 antifibrotic 691 00:26:00,134 --> 00:26:02,474 as well as the different permutations of this 692 00:26:02,534 --> 00:26:04,934 because I think the patient's preferences are really 693 00:26:04,934 --> 00:26:06,315 important. Some patients 694 00:26:06,694 --> 00:26:08,934 feel okay and they really don't like taking 695 00:26:08,934 --> 00:26:11,400 medications, can't convince them to take anything. And 696 00:26:11,400 --> 00:26:13,079 then on the other end, you have patients 697 00:26:13,079 --> 00:26:15,240 who want to be as aggressive as possible 698 00:26:15,240 --> 00:26:17,480 and will take everything at once and a 699 00:26:17,480 --> 00:26:19,240 lot of patients fall in between them. So 700 00:26:19,240 --> 00:26:21,480 I think that shared decision making is really 701 00:26:21,480 --> 00:26:21,980 key. 702 00:26:22,615 --> 00:26:24,294 Yeah. I love that. I feel like more 703 00:26:24,294 --> 00:26:26,294 and more as I go through fellowship, the 704 00:26:26,294 --> 00:26:28,534 theme in pulmonary in particular, where we don't 705 00:26:28,534 --> 00:26:31,015 have the luxury of the 20,000 patient trials 706 00:26:31,015 --> 00:26:33,494 that the cardiology gets is shared decision making. 707 00:26:33,494 --> 00:26:35,994 I feel like where these episodes always end. 708 00:26:37,690 --> 00:26:39,929 So thank you for reminding me that patient 709 00:26:39,929 --> 00:26:40,669 first approach. 710 00:26:40,970 --> 00:26:41,789 Yes, exactly. 711 00:26:42,250 --> 00:26:44,009 So this has been a great discussion. Thanks 712 00:26:44,009 --> 00:26:45,869 for bringing the paper to us, Robert. 713 00:26:46,250 --> 00:26:48,250 As we wrap up here, I'm wondering what 714 00:26:48,250 --> 00:26:50,029 is your big picture takeaway 715 00:26:50,434 --> 00:26:52,194 from the FiberNeur trial? What do you wanna 716 00:26:52,194 --> 00:26:53,494 leave our listeners with? 717 00:26:54,515 --> 00:26:55,015 Yeah. 718 00:26:55,554 --> 00:26:57,794 The top line result that I'll carry in 719 00:26:57,794 --> 00:26:59,875 my head forward is that neuron don't last 720 00:26:59,875 --> 00:27:01,394 as a new tool in our arsenal to 721 00:27:01,394 --> 00:27:02,855 slow the progression of IPF, 722 00:27:03,340 --> 00:27:06,059 Importantly worked alone or in combination of other 723 00:27:06,059 --> 00:27:06,559 endofibrotics 724 00:27:06,940 --> 00:27:09,180 with a favorable side effect profile, but it 725 00:27:09,180 --> 00:27:12,160 didn't improve mortality, exacerbations, or quality of life. 726 00:27:12,940 --> 00:27:16,125 Yeah. I love that. Nice, succinct summary. Doctor 727 00:27:16,125 --> 00:27:18,205 Ng, similarly, is there anything you wanna make 728 00:27:18,205 --> 00:27:20,625 sure that we take away from this conversation 729 00:27:20,684 --> 00:27:21,744 or from this paper? 730 00:27:22,045 --> 00:27:23,644 In summary, I would say in a random 731 00:27:23,644 --> 00:27:25,345 last, as Rob has mentioned, 732 00:27:25,644 --> 00:27:27,265 was effective as monotherapy 733 00:27:27,644 --> 00:27:30,130 and as add on therapy in patients already 734 00:27:30,130 --> 00:27:31,750 taking background antifibrotic 735 00:27:32,049 --> 00:27:34,710 therapy who have idiopathic pulmonary fibrosis. 736 00:27:35,410 --> 00:27:36,070 The recommendation 737 00:27:36,450 --> 00:27:39,269 is to start eighteen milligrams for all patients 738 00:27:39,410 --> 00:27:41,509 with idiopathic pulmonary fibrosis. 739 00:27:42,130 --> 00:27:43,190 In those who 740 00:27:43,605 --> 00:27:45,865 incur side effects, namely GI, 741 00:27:46,164 --> 00:27:48,825 dose reduction to nine milligrams can be considered 742 00:27:48,884 --> 00:27:51,545 in those who are not taking background therapy 743 00:27:51,605 --> 00:27:54,404 or already taking nintenib. But in those who 744 00:27:54,404 --> 00:27:57,365 are taking profenadone, dose reduction is not an 745 00:27:57,365 --> 00:27:59,224 option due to the drug infraction 746 00:27:59,789 --> 00:28:00,529 with nerandomlast 747 00:28:00,830 --> 00:28:02,130 rendering the drug ineffective. 748 00:28:02,910 --> 00:28:04,690 A huge benefit though with nerandomlast 749 00:28:04,990 --> 00:28:07,789 is that lab monitoring is not necessarily compared 750 00:28:07,789 --> 00:28:10,990 to the traditional anti fibrotics, which is really 751 00:28:10,990 --> 00:28:12,450 important for our patients. 752 00:28:13,005 --> 00:28:15,484 And while we still don't have anything to 753 00:28:15,484 --> 00:28:18,285 reverse or stop disease progression, I think we 754 00:28:18,285 --> 00:28:19,825 are moving in the right direction. 755 00:28:20,365 --> 00:28:23,724 As I alluded to in the podcast last 756 00:28:23,724 --> 00:28:26,204 time when we discussed the INPULSIS trial, I 757 00:28:26,204 --> 00:28:27,904 do think the management of ILDs 758 00:28:28,450 --> 00:28:29,670 will require a multimodal 759 00:28:30,049 --> 00:28:33,090 approach akin to many other complex diseases from 760 00:28:33,090 --> 00:28:36,450 diabetes and hypertension to respiratory diseases such as 761 00:28:36,450 --> 00:28:37,430 asthma and COPD. 762 00:28:38,690 --> 00:28:39,910 Nintedib and prophenidone 763 00:28:40,210 --> 00:28:41,509 slow down disease progression. 764 00:28:42,055 --> 00:28:43,515 The addition of nerandomilast 765 00:28:43,894 --> 00:28:45,434 slows this down even more. 766 00:28:45,815 --> 00:28:48,295 There continues to be numerous studies that are 767 00:28:48,295 --> 00:28:51,654 underway to continue to push the boundaries further 768 00:28:51,654 --> 00:28:53,275 towards more effective treatments. 769 00:28:53,734 --> 00:28:56,055 Other trials have shown promise in phase two 770 00:28:56,055 --> 00:28:58,799 trials that halt a PC decline and even 771 00:28:58,799 --> 00:29:01,039 potentially improve it in trials such as the 772 00:29:01,039 --> 00:29:02,660 ELEVATE and WHISPLPF trials. 773 00:29:03,119 --> 00:29:05,119 But more to come, and hopefully we'll have 774 00:29:05,119 --> 00:29:07,599 the opportunity to meet again with even more 775 00:29:07,599 --> 00:29:08,579 exciting updates. 776 00:29:09,039 --> 00:29:10,079 Yeah. I would love that. 777 00:29:10,924 --> 00:29:13,265 Careful, what you promised, Doctor. Ng, 778 00:29:13,644 --> 00:29:15,505 you're gonna find yourself very busy. 779 00:29:17,005 --> 00:29:18,605 Problem to have. We would love to have 780 00:29:18,605 --> 00:29:20,365 you back on both of you back on 781 00:29:20,365 --> 00:29:20,865 later, 782 00:29:21,325 --> 00:29:23,404 in the future. All right. Well, thanks everybody 783 00:29:23,404 --> 00:29:25,404 for listening. Thank you to Robert and Doctor. 784 00:29:25,404 --> 00:29:27,769 Ng for joining. That's a wrap for today's 785 00:29:27,769 --> 00:29:29,609 episode. I hope you all enjoyed it at 786 00:29:29,609 --> 00:29:31,369 home, and we will see you again soon 787 00:29:31,369 --> 00:29:32,429 for another episode.