WEBVTT NOTE This file was generated by Descript 00:00:00.030 --> 00:00:02.820 Judith: Welcome to Berry's In the Interim podcast, where we explore the 00:00:02.820 --> 00:00:06.250 cutting edge of innovative clinical trial design for the pharmaceutical and 00:00:06.250 --> 00:00:08.390 medical industries, and so much more. 00:00:08.760 --> 00:00:09.430 Let's dive in. 00:00:11.860 --> 00:00:12.889 Scott Berry: All right, wonderful. 00:00:12.940 --> 00:00:16.479 Uh, I welcome everybody to in the interim. 00:00:16.990 --> 00:00:20.780 We have a really cool, uh, session today. 00:00:21.029 --> 00:00:25.849 We are joined by, uh, two really interesting people. 00:00:26.060 --> 00:00:28.080 Uh, the first Merit Sidkovich. 00:00:29.255 --> 00:00:37.294 Who is, um, uh, at MGH and is going to come talk to us today about the 00:00:37.295 --> 00:00:42.474 Healy ALS trial and all things clinical trial science related to, to that. 00:00:42.745 --> 00:00:45.884 Uh, and we're joined by Melanie Quintana, Dr. 00:00:45.884 --> 00:00:49.235 Melanie Quintana of Berry Consultants and she has been 00:00:49.235 --> 00:00:54.405 working on the, uh, statistical analysis and design of the same ALS. 00:00:55.254 --> 00:00:56.614 Healy platform trial. 00:00:56.774 --> 00:00:58.584 So welcome, both of you. 00:01:00.364 --> 00:01:07.914 Uh, let's, let's start, Merritt, with tell me about how this trial got started. 00:01:09.670 --> 00:01:12.580 Merit Cudkowicz: Yeah, very nice to be here with Melanie and with you, Scott. 00:01:12.970 --> 00:01:18.320 You know, in about 2018, um, you know, we were thinking about how we could be 00:01:18.320 --> 00:01:23.450 more efficient in testing treatments for people living with ALS, also known as 00:01:23.450 --> 00:01:28.279 Lou Gehrig's disease, because finally there was a big pipeline of therapies. 00:01:28.890 --> 00:01:31.390 But, you know, the old fashioned way of doing one at 00:01:31.390 --> 00:01:32.650 a time was taking a long time. 00:01:33.100 --> 00:01:37.529 So we read this New England Journal of Medicine article by Janet Woodcock talking 00:01:37.530 --> 00:01:41.270 about master platform trials, and it was something we'd never heard about. 00:01:41.560 --> 00:01:45.399 And so we started to call around, and we, we really found that there was 00:01:45.399 --> 00:01:49.020 a lot of experience in it, in cancer and with the Berry Consultants Group. 00:01:49.400 --> 00:01:54.539 So we got a group together to learn from, from, um, From you guys as well 00:01:54.539 --> 00:01:58.500 as people who had run them and other diseases and the message was loud and 00:01:58.570 --> 00:02:00.340 clear that ALS was ready for that. 00:02:00.380 --> 00:02:01.699 So that's how we got started. 00:02:03.335 --> 00:02:06.655 Scott Berry: Uh, and, and I remember you came and you said, 00:02:06.734 --> 00:02:08.565 we want to be enrolling in a year. 00:02:09.345 --> 00:02:13.555 And Melanie and I looked at each other and said, uh, yeah, wow. 00:02:13.605 --> 00:02:15.515 And of course it happened. 00:02:15.904 --> 00:02:19.704 Um, uh, uh, and of course you're, you're a force behind that. 00:02:20.054 --> 00:02:26.415 So, interestingly, Melanie, so, and when it started, it started with five arms. 00:02:26.415 --> 00:02:27.134 Is that right? 00:02:28.200 --> 00:02:29.249 Merit Cudkowicz: Yes, we picked five. 00:02:29.250 --> 00:02:33.399 We, we, um, and then because of the timing of the drugs, we ended up with 00:02:33.420 --> 00:02:36.750 three first and then we added the fourth and fifth shortly afterwards. 00:02:37.245 --> 00:02:37.584 Scott Berry: Okay. 00:02:37.905 --> 00:02:45.165 So, just before this, Melanie and I worked with an IMI Uh, EU IMI 00:02:45.175 --> 00:02:49.385 funded project to do a very similar thing in Alzheimer's disease. 00:02:50.675 --> 00:02:55.935 Uh, 50 million plus euro was spent to design this trial. 00:02:56.275 --> 00:02:59.995 Beautiful trial with registries that they would enroll from. 00:03:00.445 --> 00:03:03.915 And it never brought an arm from pharma in. 00:03:04.505 --> 00:03:06.375 Uh, uh, both in this. 00:03:06.375 --> 00:03:11.435 And so you had this amazing, opening of this with five arms coming in. 00:03:12.335 --> 00:03:12.905 May. 00:03:12.965 --> 00:03:16.115 Maybe I'll ask Melanie, since you were involved in both of these 00:03:16.115 --> 00:03:17.770 efforts, what was the difference? 00:03:19.540 --> 00:03:22.120 Melanie Quintana: Oh, I think there were a lot of differences. 00:03:22.120 --> 00:03:25.680 Like you said, Scott, from the beginning, Merit, you came to us and you said, 00:03:25.680 --> 00:03:26.910 we're going to do this in a year. 00:03:26.910 --> 00:03:29.930 And I thought, Oh my goodness, but okay, let's go. 00:03:30.270 --> 00:03:33.219 And I think even from the first meeting, you could tell that there 00:03:33.220 --> 00:03:37.559 was such an energy about your group and everybody had really. 00:03:37.575 --> 00:03:49.894 And so I think that was a big, all of the people that you have merit 00:03:49.895 --> 00:03:55.055 and all of the team really supported this to be able to go quickly. 00:03:55.684 --> 00:03:59.305 and then I think a big part of it was that there was funding from the 00:03:59.305 --> 00:04:04.254 start and that it was almost like a competition for the companies to come in. 00:04:04.254 --> 00:04:06.075 But I think Merit could speak to that more. 00:04:06.075 --> 00:04:07.045 But for me, it was. 00:04:07.690 --> 00:04:11.990 the solid team that was there, everybody was just passionate about the work, 00:04:12.010 --> 00:04:16.390 everybody wanted to see this move forward, and it was just, wow, okay, 00:04:16.520 --> 00:04:18.329 we're going, this is going to happen. 00:04:19.845 --> 00:04:22.345 Merit Cudkowicz: Well, there's some, I mean, all these illnesses need speed, 00:04:22.405 --> 00:04:26.375 but, um, you know, in ALS, it's always the thought is this is such a rapid 00:04:26.385 --> 00:04:29.854 illness where people live three, three years, you know, sometimes a little 00:04:29.855 --> 00:04:32.105 longer, but you have to move fast. 00:04:32.105 --> 00:04:35.265 And we have this network that Neal's consortium with sites. 00:04:38.150 --> 00:04:41.080 It was almost like we needed to do the last 20 years of work 00:04:41.080 --> 00:04:45.559 of, of building the ALS trial network to be able to launch fast. 00:04:45.570 --> 00:04:49.220 But as Melanie said, having the funding was key, and that was a real, it was 00:04:49.220 --> 00:04:53.359 a gift from a patient I took care of, Sean Healy, for which we named the 00:04:53.359 --> 00:04:57.440 platform trial after him, where he gave us resources so that we could, 00:04:57.700 --> 00:05:02.250 For the first four companies, um, contribute some, uh, philanthropy, 00:05:02.300 --> 00:05:03.910 um, to, to get it off the ground. 00:05:03.910 --> 00:05:05.590 And as Melanie said, we made a competition. 00:05:05.590 --> 00:05:08.100 We had an RFP for the first companies to join us. 00:05:08.900 --> 00:05:10.940 So, so that helped get it off the ground. 00:05:10.940 --> 00:05:14.389 And with pharma, who, who have most of the really exciting drugs, 00:05:14.390 --> 00:05:15.510 that's who we wanted to work with. 00:05:16.725 --> 00:05:21.275 Scott Berry: So in thinking about the role of the platform and having multiple 00:05:21.275 --> 00:05:26.275 arms come in this, how many applications did you get to join the master protocol? 00:05:26.990 --> 00:05:29.710 Merit Cudkowicz: We got 33 applications in that first call. 00:05:30.135 --> 00:05:33.305 Uh, now they weren't all ready for, uh, you know, phase two trial, 00:05:33.305 --> 00:05:34.735 but they were really good ones. 00:05:34.735 --> 00:05:37.635 And we had a scientific review and picked the first five. 00:05:38.874 --> 00:05:44.485 Scott Berry: so this just points out that this is not a disease where 00:05:44.485 --> 00:05:46.354 there's one or two drugs of interest. 00:05:46.354 --> 00:05:49.894 There's a huge number of ideas in an incredibly hard book. 00:05:50.045 --> 00:05:51.115 disease to treat. 00:05:51.135 --> 00:05:57.075 But, uh, and so the part of the role was bringing in these, the many drugs, taking 00:05:57.075 --> 00:06:00.214 many shots on goal, uh, in this scenario. 00:06:00.480 --> 00:06:03.420 Merit Cudkowicz: Yes, I think the other thing that helped, um, I was just 00:06:03.430 --> 00:06:07.620 thinking about this is that before we issued the call for applications, we 00:06:07.620 --> 00:06:12.410 had a, um, I think a one day industry roundtable and then Melanie was there 00:06:12.410 --> 00:06:16.280 and we, we spoke, we invited all the companies we knew of that had drugs 00:06:16.280 --> 00:06:17.999 that might be ready for phase two. 00:06:18.469 --> 00:06:22.490 And we talked about the trial design and we, we let, we gave time for 00:06:22.490 --> 00:06:26.010 industry to voice their input in the design and things that they. 00:06:26.460 --> 00:06:30.280 might worry about or want to know about before we finalize the design. 00:06:30.290 --> 00:06:33.830 And, uh, you know, in retrospect, that was a really good thing to do. 00:06:34.270 --> 00:06:37.020 I don't know that we did it, you know, so planned out, but 00:06:37.030 --> 00:06:38.799 it was, um, a way to get buy in. 00:06:39.699 --> 00:06:40.899 Melanie Quintana: Yeah, I think you're right. 00:06:40.899 --> 00:06:45.179 I think it was very helpful that there was a convergence and a collaboration 00:06:45.179 --> 00:06:47.450 with everybody, including patients. 00:06:47.815 --> 00:06:50.914 You know, on what is the best trial design. 00:06:50.925 --> 00:06:53.965 So people knew, companies knew that if they joined the platform, 00:06:53.965 --> 00:06:57.905 they were joining the best trial design that they could do. 00:06:57.905 --> 00:07:02.104 And there wasn't a lot of argument around, you know, which end point should we use? 00:07:02.104 --> 00:07:02.925 What should we do here? 00:07:02.934 --> 00:07:09.215 Everyone just was on board that if we're joining a convergence of 00:07:09.215 --> 00:07:13.115 collaboration across key opinion leaders that was really the best design 00:07:13.115 --> 00:07:14.294 that we could have run at the time. 00:07:16.405 --> 00:07:20.555 Scott Berry: So a different groups looking to start these master protocols, 00:07:20.555 --> 00:07:26.415 it's almost like there are four stakeholders that are a key here. 00:07:26.455 --> 00:07:32.765 And if any one of these fail, the trial may not go, which are sites. 00:07:32.805 --> 00:07:37.055 You have to have the sites and you have this incredible Neal's network of sites. 00:07:38.440 --> 00:07:42.260 patients, if patients aren't interested in the trial, there's 00:07:42.260 --> 00:07:45.810 no trial, pharma and regulators. 00:07:45.820 --> 00:07:49.860 So you've touched on a little bit about patients and Sean Healy being very 00:07:49.860 --> 00:07:53.120 excited, providing funding for this. 00:07:53.349 --> 00:07:57.529 The Neal's Network, so you had this incredible ability to put 00:07:57.529 --> 00:07:59.649 this master protocol on the sites. 00:08:00.205 --> 00:08:03.015 You, so you talked about the patients you brought, you had this 00:08:03.025 --> 00:08:06.745 one day consortium with pharma and got them all excited about it. 00:08:07.065 --> 00:08:12.115 What about the fourth pillar about that, the FDA, how, what have your interactions 00:08:12.125 --> 00:08:13.875 been with the FDA on the trial? 00:08:13.875 --> 00:08:21.404 Yeah, 00:08:21.770 --> 00:08:23.900 Merit Cudkowicz: Once just with the design team. 00:08:23.900 --> 00:08:28.240 So the team from Barry Consultants and the team from MGH and Niels. 00:08:29.355 --> 00:08:34.794 to just lay out our plans, get their input, and they were so enthusiastic. 00:08:34.805 --> 00:08:35.935 This was when, Dr. 00:08:35.935 --> 00:08:37.335 Billy Dunn was in charge. 00:08:37.735 --> 00:08:40.894 We actually left the meeting where they said they hoped that one day 00:08:40.894 --> 00:08:44.195 we'd be writing papers together about this approach for neuro, 00:08:44.195 --> 00:08:48.525 neurotherapeutics and you don't usually leave a FDA meeting with that. 00:08:48.685 --> 00:08:50.445 So that was step one. 00:08:51.135 --> 00:08:54.975 And then step two, we came back with the first, four companies. 00:08:55.285 --> 00:08:58.855 And so we had a meeting all together, and we had time each 00:08:58.855 --> 00:09:02.915 company alone and time together, and we took a nice picture of that. 00:09:02.915 --> 00:09:04.775 And that was really uplifting as well. 00:09:06.585 --> 00:09:10.165 Melanie Quintana: Yeah, I'll add, you know, it can be a challenge 00:09:10.165 --> 00:09:14.115 when you're, you know, statistically speaking, you know, when you're putting 00:09:14.115 --> 00:09:19.695 forth complex or innovative features, you know, so it took work, right? 00:09:19.695 --> 00:09:23.955 Like we had lots of, for, I would say at least a year and a half, we had 00:09:23.965 --> 00:09:28.805 many iterations back and forth with the FDA, just getting them comfortable with 00:09:28.845 --> 00:09:31.005 the complex and innovative approaches. 00:09:31.350 --> 00:09:33.830 that we needed to take within the platform trial. 00:09:33.860 --> 00:09:38.180 But because we were able to do all of that up front, really the back 00:09:38.180 --> 00:09:40.930 and forth, the iteration, getting them comfortable with what we were 00:09:40.930 --> 00:09:46.629 proposing, each new industry sponsor didn't have to go and then recreate 00:09:46.640 --> 00:09:48.359 the wheel and do that all over again. 00:09:48.359 --> 00:09:52.090 So it's almost like we did all of that hard work up front to get the agency 00:09:52.090 --> 00:09:55.240 comfortable with what we were doing, and we didn't have to keep doing that 00:09:55.270 --> 00:09:57.689 over and over and over again afterward. 00:09:59.135 --> 00:10:01.544 Merit Cudkowicz: The other thing I'll add, because Mellie, you can't say this, 00:10:01.544 --> 00:10:06.010 but the respect they, um, The FDA has for the Berry Consultants Group, um, 00:10:06.020 --> 00:10:10.040 platform trial designs, probably on more, but, uh, that helped a lot because 00:10:10.040 --> 00:10:11.260 they, they want to learn about this. 00:10:11.260 --> 00:10:14.690 This is new in, in, in a lot of neurotherapeutic areas. 00:10:15.090 --> 00:10:18.409 And, uh, so it really felt like a partnership on trying to figure 00:10:18.409 --> 00:10:19.929 out how to do this in the best way. 00:10:21.040 --> 00:10:24.400 And then I'd also say that we just recently went back to share our 00:10:24.400 --> 00:10:29.890 learnings from the first five regiments and again, just the design team. 00:10:29.890 --> 00:10:33.340 And that was really positive as well. 00:10:34.725 --> 00:10:38.945 Scott Berry: so I want to touch on the five, but maybe for our listeners. 00:10:39.250 --> 00:10:44.320 Uh, are dozens of listeners out there, the, uh, Melanie, can you tell me a little 00:10:44.330 --> 00:10:48.649 bit about the, the, the, the science of the trial, the statistics, what's 00:10:48.650 --> 00:10:52.040 the design for regimen a for regimen B. 00:10:53.070 --> 00:10:58.640 Melanie Quintana: Right, so it's a shared control design, um, and parallel what we 00:10:58.640 --> 00:11:01.480 call regimens are enrolled in the design. 00:11:01.760 --> 00:11:05.279 Um, uh, industry sponsor would come in, they would be a regimen. 00:11:05.659 --> 00:11:08.380 We have sort of two part randomization. 00:11:08.439 --> 00:11:14.490 One, you are randomized to any of the available regimens, and then once you 00:11:14.520 --> 00:11:18.060 are randomized to that regimen, you will get more information about it, you would 00:11:18.060 --> 00:11:20.140 get consent to be a part of the regimen. 00:11:20.515 --> 00:11:25.415 There may be some slight minor inclusion, extra minor inclusion exclusion criteria 00:11:25.415 --> 00:11:27.135 that you need to pass for that regimen. 00:11:27.475 --> 00:11:31.295 And then you're randomized three to one active to placebo. 00:11:31.305 --> 00:11:35.735 So we're able to eliminate a lot of placebo subjects that 00:11:35.735 --> 00:11:36.885 we need to do these tests. 00:11:37.275 --> 00:11:41.404 And then we are able to share controls across the different regimens. 00:11:41.415 --> 00:11:44.844 So essentially when we had the first three regimens, it was like a 00:11:44.844 --> 00:11:49.025 one to one comparison, but we were able to get away with, you know, 75 00:11:49.055 --> 00:11:51.795 percent less placebo in doing that. 00:11:51.805 --> 00:11:55.064 So that's the, that was the main statistical efficiency 00:11:55.064 --> 00:11:56.615 is sharing those placebos. 00:11:56.935 --> 00:11:59.785 Across the different, what we call regimens. 00:12:00.115 --> 00:12:05.635 Um, and then because we have that statistical complexity or because we, 00:12:05.635 --> 00:12:09.445 we are trying to share that information, we had to develop some more creative 00:12:09.505 --> 00:12:13.555 primary analysis models that could account for potential differences in the shared 00:12:13.555 --> 00:12:16.375 controls across regimens, across time. 00:12:16.495 --> 00:12:20.425 So that's where the more innovative primary analysis methods came in, 00:12:20.425 --> 00:12:24.385 where we need to, to do some Bayesian borrowing across the, the regimen. 00:12:27.120 --> 00:12:31.169 Scott Berry: So the first five regimens have read out and that 00:12:31.179 --> 00:12:33.869 that's become public, um, within that. 00:12:34.520 --> 00:12:40.670 Um, have have you been able to address the efficiency, uh, I know originally 00:12:40.670 --> 00:12:46.020 when the trial came out, you talked about speeding the time to effective therapies 00:12:46.030 --> 00:12:48.580 by 50 percent reducing the resources. 00:12:49.439 --> 00:12:52.400 Did that, was that realized in the first five? 00:12:53.790 --> 00:12:55.530 Merit Cudkowicz: Yes, absolutely. 00:12:55.650 --> 00:13:01.515 we were able to read out these five drugs in About two and a half years, if I can. 00:13:01.525 --> 00:13:04.415 And usually you would read out, maybe one if you're lucky, 00:13:04.415 --> 00:13:06.064 maybe two in that time period. 00:13:07.305 --> 00:13:12.455 we also found that enrollment was, two or three times faster than typical trials. 00:13:12.455 --> 00:13:18.205 And I, think that's because of the, the patient group, engagement. 00:13:18.385 --> 00:13:22.435 And they're really feeling that this type of approach was very patient centered. 00:13:22.850 --> 00:13:26.449 And our patient advisory group, is really a community coming together. 00:13:26.449 --> 00:13:27.660 So that helped with enrollment. 00:13:28.739 --> 00:13:31.070 and then the costs are much less. 00:13:31.260 --> 00:13:34.800 We actually have a paper coming out too my, first and only economics 00:13:34.800 --> 00:13:38.009 paper about the cost savings. 00:13:38.209 --> 00:13:39.709 So there's more to come on that. 00:13:39.710 --> 00:13:45.459 Yes, 00:13:46.150 --> 00:13:47.780 Scott Berry: were there in the first five? 00:13:47.780 --> 00:13:52.760 And what was the, statistical significance of those controls? 00:13:52.805 --> 00:14:00.135 Melanie Quintana: Yeah, so there was only 205, I believe about 205 placebo patients, 00:14:00.964 --> 00:14:03.095 but they were used for all five regimens. 00:14:03.105 --> 00:14:06.875 So almost like a thousand patients worth of data. 00:14:06.895 --> 00:14:14.545 So those 205 placebo participants, even in those, testing of drugs almost counted. 00:14:15.445 --> 00:14:17.955 five times as much as what they were. 00:14:17.955 --> 00:14:23.005 So we're able to save, nearly 800 placebo participants in 00:14:23.005 --> 00:14:24.804 testing those five regimens. 00:14:25.170 --> 00:14:30.230 Which is a huge savings, and a huge benefit to get participants to want 00:14:30.230 --> 00:14:33.050 to be a part of the platform trial. 00:14:33.410 --> 00:14:36.999 And then there's, we'll get to this, but then there's the, those, 00:14:37.060 --> 00:14:41.229 participants all are now going into the data where we can learn more about 00:14:41.229 --> 00:14:45.300 the science of ALS and design better clinical trials, look at biomarkers. 00:14:45.310 --> 00:14:48.260 So, now because we've collected all this data within this 00:14:48.260 --> 00:14:49.990 rigorous clinical trial setting. 00:14:50.245 --> 00:14:54.345 And we, we say, you know, we're quote unquote retiring this data, 00:14:54.365 --> 00:14:57.675 but they're going to do more in retirement that they maybe ever 00:14:57.675 --> 00:14:59.855 did in the actual platform trial. 00:14:59.855 --> 00:15:03.214 So that's the other huge benefit of collecting all this 00:15:03.215 --> 00:15:04.605 data within this platform. 00:15:05.680 --> 00:15:07.880 Scott Berry: Yeah, that, uh, that's incredible. 00:15:07.880 --> 00:15:12.010 I, I know the PROACT database is such a valuable resource, but had 00:15:12.010 --> 00:15:17.020 these five arms been run in separate trials, it would be very hard to 00:15:17.020 --> 00:15:19.050 get the data together to analyze. 00:15:19.050 --> 00:15:22.920 And now you've got this growing resource of disease learning in it. 00:15:23.399 --> 00:15:26.409 So, so Merrick, the, the sixth and seventh. 00:15:27.015 --> 00:15:32.745 Regimens, uh, have read out and it's become public, uh, in that and, and 00:15:32.825 --> 00:15:35.085 papers to come on those as well. 00:15:35.085 --> 00:15:45.935 Uh, and so right now, currently, as we sit in, uh, uh, spring of 2025, 00:15:45.945 --> 00:15:47.655 there are no arms in the trial. 00:15:49.090 --> 00:15:49.260 Merit Cudkowicz: That's right. 00:15:49.735 --> 00:15:50.275 Scott Berry: No arms 00:15:50.350 --> 00:15:53.210 Merit Cudkowicz: We're working with a few companies to, uh, for 00:15:53.210 --> 00:15:56.560 the, to start new arms, but we're not enrolling in any right now. 00:15:57.030 --> 00:15:57.340 Scott Berry: Yeah. 00:15:57.950 --> 00:16:03.310 So, um, there has been, there have been articles written about the first seven, 00:16:03.570 --> 00:16:08.700 uh, from the perspective that none of them hit the predefined success boundaries. 00:16:09.019 --> 00:16:11.060 Now they're all phase two trials. 00:16:11.289 --> 00:16:14.910 Each one of them are learning a great deal and they're making decisions. 00:16:14.910 --> 00:16:19.060 There may be promising aspects to those, but they haven't hit success. 00:16:19.450 --> 00:16:23.770 So there was, uh, an article written in biospace. 00:16:24.170 --> 00:16:28.600 Um, uh, by Heather McKenzie, somewhat okay. 00:16:28.600 --> 00:16:32.429 There have been seven arms and it's been unsuccessful and I hate to say 00:16:32.429 --> 00:16:35.950 it, but almost is there something wrong with the healing trial? 00:16:36.600 --> 00:16:42.129 Um, when in some sense this is incredible progress and you're 00:16:42.129 --> 00:16:44.240 taking multiple shots on goal and as. 00:16:44.640 --> 00:16:47.960 Thomas Edison said, I, we haven't failed. 00:16:47.960 --> 00:16:50.620 We've learned 10, 000 ways that don't work. 00:16:50.620 --> 00:16:52.500 You're, you're learning and you're moving through. 00:16:52.870 --> 00:16:55.850 So what do you say to people who say, well, you had, you weren't 00:16:55.850 --> 00:16:59.740 seeing that none of the arms met success in the first seven. 00:17:01.100 --> 00:17:02.719 Merit Cudkowicz: Yeah, no, and I've heard that. 00:17:02.730 --> 00:17:06.480 And I say, first of all, ALS is a very complex disorder. 00:17:06.480 --> 00:17:10.449 And as we learn more about the biology, the therapies that come forward are 00:17:10.450 --> 00:17:12.589 going to be more likely to be successful. 00:17:12.609 --> 00:17:16.250 That, that, the number one thing is we got to understand the biology 00:17:16.250 --> 00:17:18.369 better and get even better drugs. 00:17:19.125 --> 00:17:23.405 The second thing I would say is we actually did learn a lot and of the seven, 00:17:23.865 --> 00:17:29.864 three have had some success in secondary or exploratory outcome measures, which 00:17:29.864 --> 00:17:32.804 is what you want to look at in phase two. 00:17:33.165 --> 00:17:37.674 and at least two of them are for sure going forward to phase three testing. 00:17:37.715 --> 00:17:40.865 The other one is still deciding based on the rest of the analysis. 00:17:41.875 --> 00:17:44.375 in that way, it, that is a success. 00:17:44.384 --> 00:17:48.144 It's about learning more about the drug and, pushing forward. 00:17:48.844 --> 00:17:53.425 And the third thing I'd say is we, did take, some time now, again, with Melanie 00:17:53.634 --> 00:17:58.054 and other biostatisticians help to look at what we learned about the first five 00:17:58.054 --> 00:18:03.714 and do we want to adapt the, platform trial, and we do, and maybe Melanie can 00:18:03.715 --> 00:18:07.554 talk a little bit about those adaptions, but we are going to make changes to 00:18:07.855 --> 00:18:13.504 increase, success, the probability of success, by the trial design. 00:18:14.020 --> 00:18:17.610 So again the, and we're also re looking at how we're picking drugs, 00:18:17.610 --> 00:18:20.399 and we have to really look at multiple things to get to success, 00:18:20.989 --> 00:18:22.610 the drugs as well as the trial design. 00:18:23.509 --> 00:18:23.749 Scott Berry: Yeah. 00:18:24.080 --> 00:18:24.340 Yeah. 00:18:25.129 --> 00:18:28.389 So now you took this pause, Melanie, you've been able to analyze data. 00:18:28.389 --> 00:18:32.790 What, what kind of changes moving forward in the analysis 00:18:32.790 --> 00:18:34.350 and the structure of the trial? 00:18:35.094 --> 00:18:35.554 Melanie Quintana: Yeah. 00:18:35.554 --> 00:18:40.324 So first of all, backing up when we originally designed the trial, we were 00:18:40.364 --> 00:18:43.975 so fortunate, you know, we designed trials in so many disease areas. 00:18:44.675 --> 00:18:47.855 Oftentimes, when you're designing the trial, you're making wild 00:18:47.865 --> 00:18:50.784 simulation assumptions about the endpoints in the disease area. 00:18:50.784 --> 00:18:53.215 You have no clue what's going to happen in the trial. 00:18:53.424 --> 00:18:56.424 But in ALS, we are so fortunate to have historical clinical 00:18:56.424 --> 00:18:58.324 trial databases like PROACT. 00:18:58.624 --> 00:19:02.284 Like it's a statistician's dream, honestly, to be able to jump 00:19:02.284 --> 00:19:06.175 into ALS and just dig into real data to design a clinical trial. 00:19:06.495 --> 00:19:10.714 So we were able to use that PROACT database to design the trial 00:19:10.714 --> 00:19:12.685 for the first five regimens. 00:19:13.129 --> 00:19:15.739 And then now that they've read out, we're kind of retiring that 00:19:15.739 --> 00:19:17.100 data, we're learning from it. 00:19:17.449 --> 00:19:21.780 We summarized the, the first five regimens and it was spot on 00:19:21.810 --> 00:19:23.360 to our simulation assumptions. 00:19:23.370 --> 00:19:27.659 So it, that just speaks to the benefit of historical clinical trial databases 00:19:27.659 --> 00:19:31.429 in that everybody should be putting their data so that we can learn from 00:19:31.430 --> 00:19:33.080 previous clinical trials into those. 00:19:33.600 --> 00:19:35.730 But so the simulations were spot on. 00:19:35.770 --> 00:19:38.620 I think in terms of power, we still believe that our original 00:19:38.620 --> 00:19:40.419 design was very appropriate. 00:19:40.834 --> 00:19:43.274 Um, We are looking at some things, though. 00:19:43.274 --> 00:19:47.435 We a lot in terms of potential mechanism of action. 00:19:47.445 --> 00:19:51.744 So while we still think we're very well powered with the original six month 00:19:51.744 --> 00:19:54.675 design, we do want to potentially move to. 00:19:54.685 --> 00:19:57.694 We do want to move to a longer design in case some of the 00:19:57.694 --> 00:19:59.914 treatments take longer to start. 00:19:59.915 --> 00:20:05.294 Um, we also looked at a wide range of inclusion exclusion criteria. 00:20:05.495 --> 00:20:08.655 There's this thought of like maybe we want to get faster progressors 00:20:08.685 --> 00:20:12.794 so we have more power and, and we looked at lots of different things. 00:20:12.794 --> 00:20:17.034 People are looking at, you know, NFL as an inclusion exclusion criteria. 00:20:17.355 --> 00:20:21.504 And really, you know, what we found is there's no magic bullet to get 00:20:21.534 --> 00:20:26.560 these sort of like Not too fast progressors, not too slow progressors. 00:20:26.570 --> 00:20:30.780 There's really, if you really whittle it down to that real homogeneous 00:20:30.789 --> 00:20:34.330 population, you're looking at such a small subset of the disease. 00:20:34.340 --> 00:20:39.270 So, we still felt pretty strongly with our original inclusion exclusion 00:20:39.270 --> 00:20:43.719 criteria, but again, because of potential mechanism of action, and Merrick can 00:20:43.719 --> 00:20:47.149 speak to this, you know, we wanted to try to go in a little bit earlier. 00:20:47.159 --> 00:20:51.445 We were originally randomizing up to, Three years since onset and now we're 00:20:51.485 --> 00:20:55.544 going to we're going to be looking within two years of onset So in terms 00:20:55.544 --> 00:21:00.145 of statistics and power, I think we didn't need to make many modifications 00:21:00.145 --> 00:21:04.995 But it was really about you know, the drugs and are we missing anything? 00:21:07.179 --> 00:21:09.129 Merit Cudkowicz: I'll add that, you know, since we started, you know, 00:21:09.129 --> 00:21:13.270 kind of a new biomarker came, uh, to the world of a LS and neurofilament. 00:21:13.779 --> 00:21:19.090 Um, and, um, there's been interest to, uh, and that that can predict, um, you know, 00:21:19.090 --> 00:21:23.739 speed of progression as well as possibly being a biomarker of treatment effect. 00:21:23.739 --> 00:21:28.600 So we, we, in the new, um, in what we call the, the next, uh, master protocol, we 00:21:28.600 --> 00:21:33.000 will also be stratifying by neurofilament levels, uh, to try to balance the group. 00:21:33.000 --> 00:21:33.241 So, but. 00:21:34.070 --> 00:21:37.810 You know, that didn't exist when we, in 2018, when we were designing the study. 00:21:38.100 --> 00:21:39.810 So we're adapting with learnings. 00:21:40.429 --> 00:21:43.429 Scott Berry: So, so let me ask a Merida a loaded question. 00:21:43.449 --> 00:21:46.600 A lot of companies come to us and they're interested in NFL and a 00:21:46.600 --> 00:21:48.330 lot of neurodegenerative diseases. 00:21:49.235 --> 00:21:56.274 So you mentioned it almost as a demographic biomarker at the beginning. 00:21:56.784 --> 00:22:01.215 Do you believe it's a surrogate marker of clinical benefit, 00:22:01.495 --> 00:22:04.065 um, as the patient progresses? 00:22:04.104 --> 00:22:05.815 Now, now this is not, you're 00:22:05.815 --> 00:22:11.735 not setting regulatory precedent, but as an expert in ALS, do you believe in NFL 00:22:11.735 --> 00:22:13.725 as a sort of surrogate clinical marker? 00:22:15.540 --> 00:22:19.449 Merit Cudkowicz: believe in it, I guess, uh, 50%, meaning that if it changes, 00:22:19.690 --> 00:22:23.969 yes, I think we do have a good example with a very targeted gene therapy that 00:22:23.970 --> 00:22:28.070 if you, if you decrease neurofilament, it, you have a clinical outcome. 00:22:28.379 --> 00:22:30.149 I'm not convinced yet of the opposite. 00:22:30.574 --> 00:22:32.985 that if a drug doesn't change it, that it's not going to 00:22:32.995 --> 00:22:34.745 have a clinical efficacy. 00:22:34.995 --> 00:22:39.324 I just think we don't have enough data to be confident of that. 00:22:39.405 --> 00:22:43.045 Um, uh, but I hope we'll learn, you know, we'll learn more because 00:22:43.074 --> 00:22:45.844 every clinical trial in ALS is now including neurofilament, 00:22:45.844 --> 00:22:47.155 including the platform trial. 00:22:47.634 --> 00:22:47.915 Scott Berry: Yeah. 00:22:48.064 --> 00:22:48.324 Yeah. 00:22:48.344 --> 00:22:51.245 So, amazing learnings on things like that within the trial. 00:22:51.674 --> 00:22:55.735 So, a lot of groups that are interested, uh, by the way, you're, the success 00:22:55.735 --> 00:22:59.584 you've had in the seven regimens coming in, in the time frame and all 00:22:59.584 --> 00:23:01.134 that has been absolutely incredible. 00:23:01.134 --> 00:23:07.634 But other groups that may be in cancer and in this phase two space, invariably 00:23:07.634 --> 00:23:09.624 they start thinking about phase three. 00:23:10.364 --> 00:23:15.174 Have you thought about an arm that kind of hits success that they can 00:23:15.174 --> 00:23:18.024 immediately seamlessly enroll phase three? 00:23:18.274 --> 00:23:20.344 Is that something you've thought about? 00:23:20.344 --> 00:23:22.544 Is that a possibility in the Healy trial? 00:23:23.724 --> 00:23:26.504 Merit Cudkowicz: We've been thinking about it, yeah, and we haven't designed 00:23:26.504 --> 00:23:28.165 it yet, but yes, yes, I'd like to. 00:23:28.480 --> 00:23:29.879 I'd like to keep thinking about that. 00:23:29.879 --> 00:23:31.040 We haven't designed that yet. 00:23:31.129 --> 00:23:32.340 I'd love to hear Melanie's thoughts. 00:23:32.350 --> 00:23:35.350 But I'll say we, we have also been thinking about the 00:23:35.480 --> 00:23:37.679 other end, the phase 2a end. 00:23:38.489 --> 00:23:41.499 Because we find a lot of companies with really great 00:23:41.500 --> 00:23:43.219 ideas are kind of stuck there. 00:23:43.310 --> 00:23:48.550 They can't develop that initial data on dose and biomarker effect to even get to 00:23:48.550 --> 00:23:50.580 going to the Healy ALS platform trial. 00:23:50.580 --> 00:23:55.449 So we're thinking about designing, um, an approach there and maybe 00:23:55.449 --> 00:23:57.050 linking that to the platform trial. 00:23:57.764 --> 00:23:58.514 Scott Berry: Oh, very neat. 00:23:58.824 --> 00:23:59.224 Yeah. 00:23:59.304 --> 00:23:59.804 Nice. 00:24:00.394 --> 00:24:07.210 Uh, and, and you, you have this pause right now and Are, are pharma, uh, is 00:24:07.210 --> 00:24:09.259 there still a lot of excitement about it? 00:24:09.280 --> 00:24:13.169 Uh, interest from pharma, new drugs, exciting new drugs coming? 00:24:14.360 --> 00:24:15.070 Merit Cudkowicz: Yes, there are. 00:24:15.370 --> 00:24:18.730 We're, we're, we're actually working with four companies on design. 00:24:19.020 --> 00:24:21.759 A lot of the companies don't want to share publicly that they're 00:24:21.759 --> 00:24:25.230 working with us until, you know, they have the FDA, the IND. 00:24:25.320 --> 00:24:27.150 Um, so there is lots of interest. 00:24:27.830 --> 00:24:31.600 I think in general in the ALS field, you know, the interest from, I guess, 00:24:31.600 --> 00:24:36.540 VCs and pharma kind of waxes and wanes, uh, depending on kind of recent results. 00:24:36.550 --> 00:24:40.929 So I think that, you know, some of the recent results, for example, with 00:24:40.929 --> 00:24:44.685 the Amalex trial, You know, kind of had a couple companies pulling back, 00:24:44.705 --> 00:24:48.324 but I, I think they're coming, coming back into ALS because the science 00:24:48.324 --> 00:24:49.985 again and the need is so great. 00:24:50.879 --> 00:24:52.059 Scott Berry: yeah, yeah. 00:24:52.440 --> 00:24:53.949 Uh, interesting, yeah. 00:24:54.179 --> 00:24:58.989 I, the, Melanie, when you work with a sponsor, I, a lot of, a lot of 00:24:58.999 --> 00:25:04.819 people Uh, in terms of a master protocol, um, when you work with the 00:25:04.819 --> 00:25:06.689 pharma, how do you convince them? 00:25:06.689 --> 00:25:08.219 What are they concerned about? 00:25:08.790 --> 00:25:13.960 When pharma comes in, is it hard to, to, to create an analysis plan for them? 00:25:14.299 --> 00:25:18.949 To, to, to address their arm and the statistical parts to 00:25:18.949 --> 00:25:20.419 that when pharma comes in? 00:25:21.414 --> 00:25:25.264 Melanie Quintana: You know for this platform there's not there's small 00:25:25.284 --> 00:25:35.439 customizations that we need to do when the industry part Um, you know, 00:25:35.449 --> 00:25:40.419 there's small sort of fine tuning that we have to do, but largely this this 00:25:40.429 --> 00:25:43.100 platform is master protocol driven. 00:25:43.319 --> 00:25:47.669 We try to keep everyone kind of enrolling the same population. 00:25:47.679 --> 00:25:49.689 That's important for sharing the controls. 00:25:49.959 --> 00:25:50.939 We try to the visits. 00:25:50.940 --> 00:25:54.120 The schedule of assessments are all very similar. 00:25:54.120 --> 00:25:57.899 So for the most part, I think we've done a good job up front. 00:25:58.385 --> 00:26:03.945 And explaining to the partners, you know, why this is the best way to go. 00:26:04.254 --> 00:26:08.545 Um, not forcing them, not having them come in and say, like, you will do this 00:26:08.565 --> 00:26:09.974 if you want to be a part of our platform. 00:26:09.975 --> 00:26:13.154 We try to, like, bring them along, we show them the simulations, we show 00:26:13.154 --> 00:26:14.874 them why this is the best way to go. 00:26:15.125 --> 00:26:18.735 And for the most part, I would say that's pretty smooth sailing. 00:26:19.485 --> 00:26:24.054 The hardest part, I, I don't know what you think Merit, but my opinion is the 00:26:24.054 --> 00:26:29.504 hardest part is the inclusion exclusion, is, is really like negotiating and making 00:26:29.504 --> 00:26:33.975 sure that we can get that to be quite synergistic across all of the regiments. 00:26:34.294 --> 00:26:38.205 Every industry partner comes in with their like small inclusion exclusion that they 00:26:38.205 --> 00:26:43.044 want to add and we need to really make sure it's necessary, um, for safety or 00:26:43.044 --> 00:26:46.014 for mechanism of action regions, reasons. 00:26:46.969 --> 00:26:47.239 Scott Berry: Hmm. 00:26:47.465 --> 00:26:48.185 Merit Cudkowicz: Yeah, I agree. 00:26:48.215 --> 00:26:51.224 Those are really the two only ones that would make sense to 00:26:51.224 --> 00:26:52.824 change it for in a platform trial. 00:26:53.620 --> 00:26:54.020 Scott Berry: Hmm. 00:26:54.440 --> 00:26:54.840 Interesting. 00:26:55.070 --> 00:27:00.080 Well, I, it's, it's uh, really neat that you've come in the interim. 00:27:00.500 --> 00:27:02.690 Uh, of the trial with this pause. 00:27:02.690 --> 00:27:05.050 I know you have a lot of exciting things coming forward. 00:27:05.270 --> 00:27:07.159 I want to congratulate both of you. 00:27:07.159 --> 00:27:10.540 It's amazing clinical trial science, amazing thing for ALS. 00:27:10.820 --> 00:27:14.940 It's also moved other disease areas forward. 00:27:14.940 --> 00:27:17.870 It's set this incredible example. 00:27:18.070 --> 00:27:20.550 So Merit, congratulations to you. 00:27:20.780 --> 00:27:23.040 Melanie, congratulations on this work. 00:27:23.360 --> 00:27:27.139 And thank you both very much for joining in the interim. 00:27:28.274 --> 00:27:28.884 Merit Cudkowicz: Thank you, Scott. 00:27:28.955 --> 00:27:29.584 Thank you, Melanie. 00:27:29.884 --> 00:27:30.634 Melanie Quintana: Yeah, thank you.