1 00:00:01,040 --> 00:00:04,120 Welcome to KD GO Conversations in Nephrology. 2 00:00:04,480 --> 00:00:08,240 This episode in our complement mediated kidney disease series 3 00:00:08,440 --> 00:00:13,520 titled Advancing Research and Novel therapies for C3G is 4 00:00:13,520 --> 00:00:18,200 provided by KD Go and supported by Apellis and Sobi. 5 00:00:18,600 --> 00:00:20,920 Here's your host, Doctor Carla Nester. 6 00:00:21,320 --> 00:00:24,840 Hello and welcome to K Deagle Conversations in Nephrology. 7 00:00:25,280 --> 00:00:28,160 I'm Doctor Carlin Nester, professor of internal medicine 8 00:00:28,160 --> 00:00:31,520 and Pediatrics, Stead Family Children's Hospital, University 9 00:00:31,520 --> 00:00:35,720 of Iowa, and joining me to discuss advancing research and 10 00:00:35,720 --> 00:00:39,960 novel therapies for C3G is Doctor Nicole Vandekar. 11 00:00:40,080 --> 00:00:43,960 Dr. Vandekar is a pediatric nephologist at Rabud University 12 00:00:44,000 --> 00:00:48,040 Medical Center 9 Megan, the Netherlands and her clinical and 13 00:00:48,040 --> 00:00:52,000 research interests include thrombotic microangiopathy and 14 00:00:52,000 --> 00:00:54,360 the complement mediated kidney diseases. 15 00:00:54,840 --> 00:00:57,440 Dr. Vandekar, welcome to this podcast. 16 00:00:57,680 --> 00:01:01,560 Thank you, Doctor Nestor, it's a pleasure to be in this podcast. 17 00:01:01,760 --> 00:01:04,720 Let's begin our discussion today with the first question. 18 00:01:05,120 --> 00:01:09,240 Let's start with your view of what the next decade as compared 19 00:01:09,240 --> 00:01:13,320 to the last decade of course in therapeutics will look like in 20 00:01:13,320 --> 00:01:16,200 the treatment of C3G. Well, thank you for this 21 00:01:16,200 --> 00:01:18,400 question. I think this will be really 22 00:01:18,400 --> 00:01:22,760 exciting decade which you are going into because now we can 23 00:01:22,760 --> 00:01:26,560 make diagnosed by kidney biopsy and C3G and we have already 24 00:01:26,560 --> 00:01:30,040 supported the therapy which we know as far as blockades and low 25 00:01:30,040 --> 00:01:32,400 salt diet. And we have already four years 26 00:01:32,400 --> 00:01:36,000 the immune suppressive treatments as Prednisone an MMF. 27 00:01:36,440 --> 00:01:40,360 But that is all non targeted treatment and you can read all 28 00:01:40,360 --> 00:01:42,880 these protocols in the Kadigo guidelines for example. 29 00:01:42,880 --> 00:01:47,640 But what is now intriguing is that we have now the first time 30 00:01:47,640 --> 00:01:50,840 targeted treatment available for C3 gene and that's because of 31 00:01:50,840 --> 00:01:54,640 those two new drugs which have now entered and then they ended 32 00:01:54,640 --> 00:01:57,080 almost at clinical trials. And then for the first time we 33 00:01:57,080 --> 00:02:00,240 have a targeted therapy which will talk the overactive 34 00:02:00,240 --> 00:02:03,560 complement alternative pathway. As we know and we heard before, 35 00:02:03,760 --> 00:02:05,360 this is the drug fiber of the disease. 36 00:02:05,360 --> 00:02:09,800 So this next decades having these complement aminipeties 37 00:02:09,800 --> 00:02:12,160 available for the treatment will be exciting. 38 00:02:12,280 --> 00:02:16,120 And I think it will lead to less chronic renal damage, less end 39 00:02:16,120 --> 00:02:20,120 stage kidney failure and hope for those C3G patients who need 40 00:02:20,120 --> 00:02:23,400 a kidney transplant and hope for a better future for all C3 41 00:02:23,400 --> 00:02:25,880 patients. So I think this next decade will 42 00:02:25,880 --> 00:02:28,560 be really promising. I think you're exactly right. 43 00:02:28,560 --> 00:02:31,280 This idea of targeted therapeutics for the first time 44 00:02:31,280 --> 00:02:33,880 in our lives in this set of diseases is amazing. 45 00:02:34,480 --> 00:02:37,440 A small question and and I don't want that you to have to think 46 00:02:37,440 --> 00:02:40,200 about too hard, but do you think there are going to be issues 47 00:02:40,200 --> 00:02:42,640 about how to use them? For instance, are you going to 48 00:02:42,640 --> 00:02:45,600 consider primary therapy or are you going to consider whether 49 00:02:45,600 --> 00:02:49,520 you have to do XY or Z first? I think for us as conditions, it 50 00:02:49,520 --> 00:02:54,680 will be very important to draft good protocol when to use these 51 00:02:54,680 --> 00:02:58,720 new drugs, for whom, on which conditions and how to follow 52 00:02:58,720 --> 00:03:00,480 them up and how to monitoring them. 53 00:03:00,640 --> 00:03:03,560 Because in the trials the patients were not mostly primary 54 00:03:03,560 --> 00:03:06,120 having the disease for only a couple of weeks or months. 55 00:03:06,360 --> 00:03:09,360 Some were already having them for years and entered the trial. 56 00:03:09,360 --> 00:03:12,960 So I think there will be definitely people who can use it 57 00:03:13,080 --> 00:03:15,760 in the first weeks of the disease, but then really well 58 00:03:15,760 --> 00:03:18,840 guided by protocols, I guess it would be the criteria to use 59 00:03:18,840 --> 00:03:20,280 for. Yeah, I think that's an 60 00:03:20,280 --> 00:03:23,200 excellent approach, this idea of developing protocols. 61 00:03:23,400 --> 00:03:26,320 So then the next question, which is a little bit unfair, you 62 00:03:26,320 --> 00:03:29,240 know, because obviously neither one of us are pharmaceutical 63 00:03:29,240 --> 00:03:31,840 people. But when designing these trials, 64 00:03:31,920 --> 00:03:34,440 you know, for these agents, what's your impression of how 65 00:03:34,440 --> 00:03:38,120 the sponsors decided upon the endpoints that they decided 66 00:03:38,120 --> 00:03:40,240 upon? Well, I was not involved 67 00:03:40,440 --> 00:03:44,240 designing the clinical trials, but I participated as you as 68 00:03:44,240 --> 00:03:47,720 well in an international working group organized by the Kidney 69 00:03:47,720 --> 00:03:52,600 Health Initiative in 2021 to address the challenges needed to 70 00:03:52,600 --> 00:03:56,560 say what do we need from this trials and what outcome do we 71 00:03:56,560 --> 00:03:58,360 need and what are the best endpoints. 72 00:03:58,480 --> 00:04:02,000 And we had a lot of discussions in working groups and it went 73 00:04:02,000 --> 00:04:04,800 back and forth and we came actually at the end we came up 74 00:04:04,800 --> 00:04:08,960 with three endpoints which might for C3G might be value valuable. 75 00:04:09,400 --> 00:04:11,920 And those are also endpoints you see in the trials. 76 00:04:12,040 --> 00:04:14,920 And for me I think the most important one is proteinuria. 77 00:04:15,120 --> 00:04:18,800 It's a risk marker for disease progression across various 78 00:04:18,800 --> 00:04:22,200 glomerular disorders. So not only C3G and we know that 79 00:04:22,280 --> 00:04:25,280 large treatment effects on proteinuria are believed to 80 00:04:25,280 --> 00:04:28,200 predict treatment effects on disease progression. 81 00:04:28,320 --> 00:04:33,320 If you then look at C3G, then we have not that much data in time 82 00:04:33,320 --> 00:04:35,160 how patients are doing on the treatments. 83 00:04:35,160 --> 00:04:38,280 But we see that from cohorts in the United Kingdom and also from 84 00:04:38,280 --> 00:04:41,640 Iowa that if, if we can reduce the proteinuria and if you can 85 00:04:41,680 --> 00:04:45,000 reduce 50% or even more, I think then it will at the end will 86 00:04:45,000 --> 00:04:48,840 benefit also your EGFR, so your kidney function and it will at 87 00:04:48,840 --> 00:04:51,240 the end will be of health for your kidney function. 88 00:04:51,360 --> 00:04:54,520 The problem is for proteinuria that it's not really an end 89 00:04:54,520 --> 00:04:57,120 point which is much used in clinical studies. 90 00:04:57,120 --> 00:05:00,120 So is it then good, Is it a bad end point? 91 00:05:00,120 --> 00:05:03,080 I think it's the best we have at the moment and I think you would 92 00:05:03,080 --> 00:05:05,600 expect an effect at six months at least. 93 00:05:06,040 --> 00:05:09,400 So for that, I think it will be a good endpoint and the best we 94 00:05:09,400 --> 00:05:12,000 have at the moment. Of course, if you ask in our 95 00:05:12,000 --> 00:05:15,080 group as clinicians, we also know that proteinuria can be 96 00:05:15,080 --> 00:05:17,960 difficult because we are aware that of course if you have 97 00:05:18,000 --> 00:05:20,720 sclerotic regions in your kidney, you also have 98 00:05:20,720 --> 00:05:23,040 proteinuria. And together with declining 99 00:05:23,040 --> 00:05:25,600 kidney function, we know that this is different proteinuria, 100 00:05:25,600 --> 00:05:28,080 this is proteinuria because of fibrosis. 101 00:05:28,080 --> 00:05:32,040 And so this will always be an issue having proteinuria as an 102 00:05:32,040 --> 00:05:34,080 endpoint. But I think looking at 103 00:05:34,080 --> 00:05:37,080 creatinine function, at kidney function and looking probably 104 00:05:37,120 --> 00:05:39,120 also at Histology, it might help. 105 00:05:39,120 --> 00:05:41,360 So this I think proteinuria is a good one. 106 00:05:41,600 --> 00:05:45,160 And next we have the EGFR. We discussed it as well in our 107 00:05:45,160 --> 00:05:47,800 working group. And of course, you would expect 108 00:05:47,800 --> 00:05:51,720 if the inflammation in your kidney caused by the overactive 109 00:05:51,720 --> 00:05:54,880 compromise activation will decline by using these drugs, 110 00:05:54,880 --> 00:05:57,920 you could imagine that your kidney function will in time 111 00:05:58,040 --> 00:06:02,800 improve and the slope of your EGFR will then get less steep. 112 00:06:02,800 --> 00:06:04,600 So your kidney function will improve. 113 00:06:04,640 --> 00:06:07,960 We don't have data retrospectively data to see what 114 00:06:07,960 --> 00:06:09,520 would be the best follow up time. 115 00:06:09,840 --> 00:06:13,040 But I think also here six months, it's fair to mention 116 00:06:13,240 --> 00:06:17,040 that you probably would not need a very deterioration of your 117 00:06:17,360 --> 00:06:19,800 EGFR. Because if that's the case, if 118 00:06:19,800 --> 00:06:24,160 your EGFR is derivating of going badly with the new drugs, you 119 00:06:24,160 --> 00:06:27,040 might wonder if something is wrong and you have to rethink 120 00:06:27,040 --> 00:06:29,480 again. So that's very important I 121 00:06:29,480 --> 00:06:31,320 think. And then you have the Histology. 122 00:06:31,520 --> 00:06:34,840 It's a rare disease and you only do your biopsy if you think 123 00:06:34,880 --> 00:06:37,600 really it's needed. So we don't know what we have to 124 00:06:37,600 --> 00:06:40,720 expect in kidney biopsies. You might think the new 125 00:06:40,720 --> 00:06:43,080 complement blockers inhibit C3 activation. 126 00:06:43,120 --> 00:06:46,560 So there might be a reduction in C3 deposits in the kidney and 127 00:06:46,560 --> 00:06:50,080 you might think in time you will be seeing that in US pathology. 128 00:06:50,440 --> 00:06:53,640 But that means that you have to re biopsy patients again. 129 00:06:53,920 --> 00:06:57,320 And I think this is something which we really need to think of 130 00:06:57,360 --> 00:06:59,920 if we want to do it and what we want to see. 131 00:07:00,040 --> 00:07:04,800 So I think what we see in the trials is that they looked at 132 00:07:04,800 --> 00:07:08,600 histopathology and had that was mostly the secondary endpoint 133 00:07:08,600 --> 00:07:11,920 and they had for example, they had an histological activity 134 00:07:11,920 --> 00:07:15,360 index. But in this score there's also a 135 00:07:15,360 --> 00:07:17,720 necrosis or fibrosis been mentioning. 136 00:07:17,720 --> 00:07:21,600 So we have to define what do we want to see in histopathology, 137 00:07:21,600 --> 00:07:25,640 which could improve the kidney health and probably the deposits 138 00:07:25,680 --> 00:07:29,480 is one of the most important things, but less fibrosis if 139 00:07:29,480 --> 00:07:32,320 there's already something there would be benefit as well. 140 00:07:32,520 --> 00:07:34,960 Yeah, I think all of your points are very important. 141 00:07:34,960 --> 00:07:38,320 I think we weren't as fortunate as, for instance, IGA to have 142 00:07:38,320 --> 00:07:42,040 that proteinuria as already a selected surrogate endpoint for 143 00:07:42,040 --> 00:07:45,040 our regulatory agencies. And when you think about the 144 00:07:45,040 --> 00:07:48,720 GFR, you can't wait, you know, the years it takes for the GFR 145 00:07:48,720 --> 00:07:52,240 to decline enough for you to get to dialysis, right. 146 00:07:52,240 --> 00:07:55,440 So you have to think about, you know, what measure of the GFR 147 00:07:55,440 --> 00:07:56,800 are you going to pay attention to? 148 00:07:56,800 --> 00:07:58,800 And you kind of already brought run up the important part 149 00:07:58,800 --> 00:08:01,440 because one of my questions was going to be if you rely on 150 00:08:01,440 --> 00:08:04,400 Histology, which certainly the animal models would have 151 00:08:04,400 --> 00:08:07,840 supported that if you stop the alternative or if you block the 152 00:08:07,840 --> 00:08:10,720 alternative pathway that maybe the Histology goes away. 153 00:08:10,880 --> 00:08:14,320 That means you have to go back to rebiopsy 2 small questions 154 00:08:14,320 --> 00:08:16,440 about and they're actually not small questions, but so you've 155 00:08:16,440 --> 00:08:18,440 already told me you would rebiopsy. 156 00:08:18,520 --> 00:08:21,160 Are your patients in general going to agree that that's OK? 157 00:08:21,880 --> 00:08:26,600 I think I would rebiopsy if I don't see enough improvement in 158 00:08:26,600 --> 00:08:30,920 proteinuria or if I hardly see any improvement in proteinuria. 159 00:08:31,280 --> 00:08:35,360 And I would also rebiopsy if I see the kidney function is 160 00:08:35,360 --> 00:08:37,480 declining. This is really for me a must to 161 00:08:37,480 --> 00:08:39,440 biopsy because it has consequences. 162 00:08:39,520 --> 00:08:42,679 If everything is going well, then you might wonder are we 163 00:08:42,679 --> 00:08:45,080 going to biopsy? And this is a difficult point 164 00:08:45,640 --> 00:08:49,720 because we should in the ideal world if biopsies would not do 165 00:08:49,720 --> 00:08:53,240 any harm, if it would be easy doing it, I think it would be 166 00:08:53,360 --> 00:08:57,160 good to do because we could see what the effect is in time of 167 00:08:57,160 --> 00:08:59,200 these new drugs on the histopathology. 168 00:08:59,200 --> 00:09:03,280 But that might be difficult to get patients and also conditions 169 00:09:03,560 --> 00:09:06,360 into re biopsy when things are going well. 170 00:09:06,760 --> 00:09:07,920 Yeah, I think you're exactly right. 171 00:09:07,920 --> 00:09:10,320 But you also make the point that we need the real world 172 00:09:10,320 --> 00:09:12,520 experience to help us solve some of these issues. 173 00:09:12,600 --> 00:09:16,880 So perhaps you can share a brief overview of the clinical trial 174 00:09:16,880 --> 00:09:19,520 results in general. I know some of that, like you've 175 00:09:19,520 --> 00:09:21,600 said has been published and some of them are are waiting for 176 00:09:21,600 --> 00:09:23,760 publication. But if you wanted to share just 177 00:09:23,760 --> 00:09:25,600 a little capsule of that for our listeners. 178 00:09:25,760 --> 00:09:28,880 Well, it already started a couple of years ago with I think 179 00:09:28,880 --> 00:09:32,160 the first international trial on complement blockade in C3G was 180 00:09:32,160 --> 00:09:35,040 the Avacupan trial and it was a phase two trial. 181 00:09:35,160 --> 00:09:38,640 Avakopan, we know now because it's now implemented in 182 00:09:38,640 --> 00:09:43,600 anchovasculitis treatment, but it's an oral blocker of the C5A 183 00:09:43,600 --> 00:09:48,720 receptor blocking the effect of C5A and it was thought it might 184 00:09:48,720 --> 00:09:52,760 have a role in C3G and it was designed really good, I mean 185 00:09:52,760 --> 00:09:56,040 double-blind placebo-controlled. And the endpoint was that we 186 00:09:56,040 --> 00:09:59,480 come to Histology. Again, the endpoint was an an 187 00:09:59,480 --> 00:10:04,000 improvement in histological activity at six months of using 188 00:10:04,000 --> 00:10:06,400 the product and this endpoint was not achieved. 189 00:10:06,480 --> 00:10:09,760 I mean there was no significant difference between avacopon and 190 00:10:09,760 --> 00:10:13,200 placebo, although there was reduction in proteinuria by 191 00:10:13,200 --> 00:10:16,040 those who were treated by Avacopon in comparison with 192 00:10:16,040 --> 00:10:19,400 those with placebo. But this trial did not made it 193 00:10:19,400 --> 00:10:21,800 further on. And then we had I think mostly 194 00:10:21,800 --> 00:10:25,080 at the same time actually there was a trial also a multicentral 195 00:10:25,080 --> 00:10:28,200 international trial on the Nicopon and that's a small 196 00:10:28,200 --> 00:10:32,120 molecule inhibitor of the complement factor D of the also 197 00:10:32,120 --> 00:10:35,760 of the alternative pathway. I mean not also because Avacupon 198 00:10:35,760 --> 00:10:39,360 is targeting the terminal pathway but the Nicopon is more 199 00:10:39,360 --> 00:10:43,640 upstream and that Nicopon is cleaving factor being it 200 00:10:43,640 --> 00:10:47,320 prevents cleavage of factor B and therefore it reduces the C3 201 00:10:47,320 --> 00:10:51,080 confratase formation which is seen as the culprit of C3G. 202 00:10:51,160 --> 00:10:54,360 And this trial was a phase two trial also double-blind, 203 00:10:54,400 --> 00:10:58,120 placebo-controlled but the efficacy was found to be 204 00:10:58,120 --> 00:11:00,760 limited. It was probably failing 205 00:11:00,760 --> 00:11:04,000 achievement in complement inhibition and although there 206 00:11:04,080 --> 00:11:07,440 were some patients showing a decline in proteinuria, I think 207 00:11:07,440 --> 00:11:10,160 it was not showing good results. So it was stopped. 208 00:11:10,360 --> 00:11:13,920 So and then I think where we all have been waiting for and would 209 00:11:13,920 --> 00:11:17,720 we see those results of two phase three trials of complement 210 00:11:17,720 --> 00:11:20,480 inhibitors targeting at the level of C3. 211 00:11:20,480 --> 00:11:24,040 So at the C3 confratase, those are the iptacupon and the 212 00:11:24,040 --> 00:11:28,360 pexitacupon and both trials have reached down the occlusion rate 213 00:11:28,360 --> 00:11:32,160 of patients and they are finalized or getting finalized 214 00:11:32,600 --> 00:11:36,320 and are almost ready or far ready to publish their results. 215 00:11:36,480 --> 00:11:39,760 And I think Iptacopan for example, an oral factor B 216 00:11:39,760 --> 00:11:43,960 inhibitor selectively blocks the formation of the C3 comfortase 217 00:11:43,960 --> 00:11:47,240 of the alternative pathway. This phase three trial has been 218 00:11:47,240 --> 00:11:50,280 performed in adults and this is now already the drug which is 219 00:11:50,280 --> 00:11:54,040 registered because of the results by the FDA and the EMA 220 00:11:54,240 --> 00:11:56,840 in the treatment of C3G in adults. 221 00:11:57,360 --> 00:11:59,960 And we have to await for the adolescence trial which is still 222 00:11:59,960 --> 00:12:03,080 going on, but already very far ahead for their results. 223 00:12:03,200 --> 00:12:07,280 So then we have Pexitacopun, it's AC three blocker activation 224 00:12:07,280 --> 00:12:11,960 level of C3 and this drug actually acts at C3 and 225 00:12:12,120 --> 00:12:16,400 therefore acts on all three complement pathways including 226 00:12:16,400 --> 00:12:18,720 the alternative pathway. And that is a drug you need to 227 00:12:18,720 --> 00:12:20,880 give subcutaneously twice weekly. 228 00:12:21,040 --> 00:12:25,200 And for this, this phase three trial is in adolescence and in 229 00:12:25,200 --> 00:12:27,560 adults. So they combine it and it's in 230 00:12:27,560 --> 00:12:32,760 C3G, but they have also primary immune complex MPGN and they 231 00:12:32,760 --> 00:12:37,040 have also included patients who are known with C3G and but have 232 00:12:37,040 --> 00:12:41,200 already a renal transplants. And actually those drugs have 233 00:12:41,200 --> 00:12:44,720 already shown good results as you're probably aware of. 234 00:12:44,920 --> 00:12:49,320 And I think the design was for both trials was they all had a 235 00:12:49,480 --> 00:12:55,160 six months, so 26 weeks or placebo or drug and then after 236 00:12:55,160 --> 00:12:58,400 26 weeks all got the drug. And I think the results have 237 00:12:58,400 --> 00:13:01,320 been published for the first six months of both drugs. 238 00:13:01,840 --> 00:13:03,480 Yeah, so thank you for that overview. 239 00:13:03,560 --> 00:13:06,520 If you are just tuning in, you're listening to the K Deagle 240 00:13:06,520 --> 00:13:11,160 podcast on advancing research and novel therapies in C3G. 241 00:13:11,520 --> 00:13:15,760 I'm Doctor Carla Nester and I'm speaking with Professor Nicole 242 00:13:15,800 --> 00:13:18,960 Vandekar, Pediatric Nephrology 9. 243 00:13:18,960 --> 00:13:22,280 Megan, so I'm going to ask you and and I might be able to guess 244 00:13:22,280 --> 00:13:25,080 since you're a pediatric nephrologist, can you share with 245 00:13:25,080 --> 00:13:27,880 us some of the distinguishing features between the studies 246 00:13:27,880 --> 00:13:31,280 that end up being important given what kind of patients 247 00:13:31,280 --> 00:13:33,920 you're approaching? Well, I think what they did in 248 00:13:33,920 --> 00:13:37,640 both studies, I think the trial design was at quite some 249 00:13:37,640 --> 00:13:40,720 similarities. Adolescents need to be above 12 250 00:13:40,720 --> 00:13:43,760 years. So we don't have data on below 251 00:13:43,760 --> 00:13:46,160 12 years. And you and I know that we see 252 00:13:46,160 --> 00:13:48,600 children which are younger than 12 years as well. 253 00:13:48,680 --> 00:13:51,360 They all wanted to have an active disease. 254 00:13:51,520 --> 00:13:55,400 They all wanted to EGFR above 30ML per minute. 255 00:13:55,480 --> 00:14:00,080 They all want to have more than 1g per gram proteinuria and 24 256 00:14:00,080 --> 00:14:03,920 hours or in first morning urine, so more than 1g per gram. 257 00:14:04,240 --> 00:14:07,920 So that makes it you already have an exclusion of patients 258 00:14:07,920 --> 00:14:11,880 who have less than this 1g or don't have the age of 12. 259 00:14:11,960 --> 00:14:13,520 You need the mandatory vaccination. 260 00:14:13,520 --> 00:14:15,240 I think that's very, very important. 261 00:14:15,480 --> 00:14:19,960 We are aware of that for the other diseases, Atos and PNH 262 00:14:20,160 --> 00:14:22,880 that you need vaccinations against the menococcal 263 00:14:23,120 --> 00:14:25,640 primococcal bacteria and hemophilus influenza. 264 00:14:25,640 --> 00:14:27,520 So that was all in both, all of them. 265 00:14:27,840 --> 00:14:31,520 So that was one thing and I think the exclusive criteria 266 00:14:31,800 --> 00:14:34,080 were almost all the same as well. 267 00:14:34,080 --> 00:14:38,200 So you were excluded if you had more than 50% sclerosis in your 268 00:14:38,200 --> 00:14:43,000 kidney biopsy secondary forms of C3G, so mostly post infectious 269 00:14:43,120 --> 00:14:45,440 and the monoclonal gammopathy were excluded. 270 00:14:45,600 --> 00:14:48,680 And you need to not have to have an exposure to other complement 271 00:14:48,680 --> 00:14:53,400 inhibitors, but you were allowed to have ACE or AOP inhibition or 272 00:14:53,400 --> 00:14:55,680 SLG 2. These were adults we're not 273 00:14:55,680 --> 00:14:57,400 allowed to use in Europe for children. 274 00:14:57,400 --> 00:14:59,520 And you, you were allowed to have Prednisone or 275 00:14:59,520 --> 00:15:03,560 corticosteroids and MMF, but you need to be on a stable regimen 276 00:15:03,640 --> 00:15:07,280 for those drugs. So those were actually having 277 00:15:07,480 --> 00:15:11,200 somehow the same results, the same inclusion or exclusion 278 00:15:11,200 --> 00:15:13,720 criteria. But of course, the way of action 279 00:15:13,720 --> 00:15:16,680 is different. One attacks factor B, the other 280 00:15:16,680 --> 00:15:21,120 attacks C3 itacupon orally, back, sitacupon subcutaneously. 281 00:15:21,400 --> 00:15:24,920 And that means that you have already have some differences 282 00:15:25,200 --> 00:15:28,080 between those drugs. If we look at the results, I 283 00:15:28,080 --> 00:15:30,680 mean the results for both studies look good. 284 00:15:30,880 --> 00:15:35,640 Iptocopon at a 35% reduction in proteinuria, change in 285 00:15:35,640 --> 00:15:38,880 proteinuria compared to the baseline and versus the placebo, 286 00:15:39,320 --> 00:15:42,360 it had a stabilization on the EGFR in 12 months. 287 00:15:42,440 --> 00:15:46,440 So that's very good. The pepsitopon where C3G and 288 00:15:46,440 --> 00:15:51,920 immune complex MPGN is included showed a reduction from 67% 289 00:15:51,920 --> 00:15:55,000 reduction in proteinuria compared to the baseline as 290 00:15:55,000 --> 00:15:58,720 compared to placebo. And they could show a small 291 00:15:58,720 --> 00:16:01,400 improvement on EGFR at six months. 292 00:16:01,880 --> 00:16:05,360 And they had already looked at more biopsies than Iptacopon at 293 00:16:05,360 --> 00:16:09,920 this time and they could show in less staining or in a lot of 0 294 00:16:09,920 --> 00:16:12,520 staining or C3G in kidney biopsies. 295 00:16:12,520 --> 00:16:18,000 So both drugs do really work as it looks on the complement over 296 00:16:18,000 --> 00:16:20,920 activation we found in C3 glomeropathy. 297 00:16:21,080 --> 00:16:22,560 So that's very good. Thank you. 298 00:16:22,560 --> 00:16:24,360 That's a very good representation of the trials. 299 00:16:24,360 --> 00:16:26,920 And I agree, you know they both work very well. 300 00:16:26,920 --> 00:16:29,880 I'm curious and I recognize we don't have data for this, but 301 00:16:29,880 --> 00:16:34,400 you mentioned they both required a 1g of urine protein, somewhat 302 00:16:34,400 --> 00:16:38,480 like the IGA world these days. Do you think once we get to real 303 00:16:38,480 --> 00:16:41,840 world we'll be interested in using it before a gram or do you 304 00:16:41,840 --> 00:16:43,600 think most of us will stick to the gram? 305 00:16:43,840 --> 00:16:45,280 Depends. I think if you have a new 306 00:16:45,280 --> 00:16:49,200 patients and it's above the 1G, I think always you start with 307 00:16:49,200 --> 00:16:53,040 ACE or OP and probably you will get already quite some patients 308 00:16:53,240 --> 00:16:58,720 having reduced Putinorium even maybe even below 0.5g a day. 309 00:16:59,080 --> 00:17:02,600 And then becomes the questions and are we going to give those 310 00:17:02,640 --> 00:17:05,240 then already immediately a complement inhibition? 311 00:17:05,560 --> 00:17:09,440 Are we doing it instead of Prednisone and MMF, which is at 312 00:17:09,440 --> 00:17:13,640 the moment standard therapy or we add first with the ACE and 313 00:17:13,640 --> 00:17:17,720 the ARP, we add Prednisone and MMF and together with complement 314 00:17:17,720 --> 00:17:20,760 inhibition. So I think this is really stuff 315 00:17:20,760 --> 00:17:23,599 to have good thinking about about what we are going to do. 316 00:17:23,599 --> 00:17:28,200 It's also, I mean those drugs are cost lots of money and if we 317 00:17:28,200 --> 00:17:31,560 want to have it available for a good treatment in our C3D 318 00:17:31,560 --> 00:17:35,200 patients, probably we should not use those complement inhibition 319 00:17:35,200 --> 00:17:39,960 drugs in those who have less than 1.5g a day and maybe even 320 00:17:40,080 --> 00:17:43,000 not with 1G. We should start with Azinarp and 321 00:17:43,000 --> 00:17:46,720 see what comes out and then progress with maybe Prednisone 322 00:17:46,720 --> 00:17:48,520 and MMF. But I know there are also 323 00:17:48,520 --> 00:17:51,360 colleagues who would like and love to start with the 324 00:17:51,360 --> 00:17:52,800 complement inhibition by the way. 325 00:17:52,880 --> 00:17:57,400 But depends if attacking of the over activated complement system 326 00:17:57,520 --> 00:18:01,520 would be enough in the first weeks of your disease. 327 00:18:01,800 --> 00:18:06,080 If there is such an inflammation already there which is broader 328 00:18:06,080 --> 00:18:09,240 than only the over activation of the complement, should we then 329 00:18:09,440 --> 00:18:12,720 still need immune suppressive drugs for example for a short 330 00:18:12,720 --> 00:18:14,480 while? What would be the best protocol? 331 00:18:14,640 --> 00:18:16,680 I think you're exactly right. I think at the end of the day, 332 00:18:16,680 --> 00:18:18,600 we still have some thinking to do on this. 333 00:18:18,600 --> 00:18:21,280 We still have to figure out, you know, is attacking inflammation 334 00:18:21,480 --> 00:18:23,280 critical? Is targeting the complement 335 00:18:23,280 --> 00:18:26,160 system critical, Is targeting the protein critical or even for 336 00:18:26,160 --> 00:18:29,000 that matter the CKD aspects. As you've kind of indicated, 337 00:18:29,000 --> 00:18:30,400 there's a number of supportive cares. 338 00:18:30,400 --> 00:18:33,760 So the final point on that might be that will the standard of 339 00:18:33,760 --> 00:18:35,680 care change? I mean, we know what has been 340 00:18:35,680 --> 00:18:39,440 set by KD GO currently we have to decide what happens next, 341 00:18:39,440 --> 00:18:41,440 don't we? And more to come, I'm sure. 342 00:18:41,440 --> 00:18:44,200 But then maybe one of the final questions I'll have for you is 343 00:18:44,200 --> 00:18:47,360 that if you could pick one or two or maybe just a very few, 344 00:18:47,360 --> 00:18:50,440 what are the biggest challenges you think that we're going to 345 00:18:50,440 --> 00:18:52,400 face? And we started this discussion 346 00:18:52,400 --> 00:18:54,600 about what's the next decade look like? 347 00:18:54,600 --> 00:18:57,240 Well, what's the next decade look like when it comes to 348 00:18:57,240 --> 00:19:01,000 challenges in this setting? I think I want to play out for 349 00:19:01,000 --> 00:19:03,600 all the clinicians treating patients with C3G. 350 00:19:03,600 --> 00:19:08,480 Unite yourself to gain more data on C3 patients and that 351 00:19:08,480 --> 00:19:11,880 treatment, whatever treatment it is, I mean if it's ACE, if it's 352 00:19:12,040 --> 00:19:15,160 AAP, if it's Prednisone corticides and we really need 353 00:19:15,160 --> 00:19:17,840 good well thought of treatment protocols. 354 00:19:18,240 --> 00:19:22,440 We have to collaborate with each other to make those protocols. 355 00:19:22,440 --> 00:19:25,480 And I think there are initiative already going on, which I really 356 00:19:25,880 --> 00:19:28,360 encourage and I really think they're very important. 357 00:19:28,360 --> 00:19:31,120 And we really have to work together on an international way 358 00:19:31,120 --> 00:19:34,280 to make this collaborative databases because then we can 359 00:19:34,280 --> 00:19:37,480 see what the landscape looks like and what the drugs will do. 360 00:19:37,560 --> 00:19:40,880 I clearly think that the standard treatment care will 361 00:19:40,880 --> 00:19:44,280 change for C3G and complement inhibition will find its place 362 00:19:44,280 --> 00:19:46,560 somewhere in those protocols as well. 363 00:19:46,560 --> 00:19:50,320 But then we'll be very that like we discussed when to start, 364 00:19:50,520 --> 00:19:53,640 which complement inhibitor use, is there a moment to stop? 365 00:19:54,000 --> 00:19:57,160 Can we stop? Do we have to treat those with 366 00:19:57,280 --> 00:20:00,480 auto antibodies against the C3 convertase, Do they need the 367 00:20:00,480 --> 00:20:04,000 same treatment as those with genetic variation for example? 368 00:20:04,040 --> 00:20:08,640 And I'm very curious can we get complete remission in all C3G 369 00:20:08,680 --> 00:20:11,680 treated patients with complement inhibition for example. 370 00:20:11,720 --> 00:20:15,000 And this is more important challenges for us as conditions 371 00:20:15,520 --> 00:20:19,280 we have clearly have to monitoring the efficacy I think 372 00:20:19,280 --> 00:20:23,000 as well and the side effects. And that's what I told earlier, 373 00:20:23,000 --> 00:20:26,760 if you don't see a benefit, let's say in 3-6 months of your 374 00:20:26,760 --> 00:20:30,120 therapy, the thing we consider maybe you need to rebiopsy 375 00:20:30,120 --> 00:20:33,840 again, you mean to think if this drug is effective enough. 376 00:20:34,040 --> 00:20:37,200 And also if you think of complement inhibition in a long 377 00:20:37,200 --> 00:20:40,800 time, is it safe in your growing child in an adolescent? 378 00:20:40,800 --> 00:20:43,400 I still don't know. I mean we have just started with 379 00:20:43,400 --> 00:20:46,920 AIDS book age of course on B&H and we are still figuring out 380 00:20:46,960 --> 00:20:50,840 and I think we are very lucky and for seeing these results of 381 00:20:50,840 --> 00:20:53,880 this new therapies. But it doesn't change anything 382 00:20:53,880 --> 00:20:56,960 on the presence of the auto antibodies against the C3 383 00:20:56,960 --> 00:20:59,960 comprotase. So at the over activation of the 384 00:20:59,960 --> 00:21:03,360 complement system, we can act with those blockers, but we can 385 00:21:03,360 --> 00:21:06,320 do not do anything on those auto antibodies. 386 00:21:06,320 --> 00:21:10,240 So that might be a challenge for future trials maybe in 387 00:21:10,240 --> 00:21:13,560 combination with complement inhibition to see if we can get 388 00:21:13,560 --> 00:21:15,960 rid of this and to auto antibodies as well. 389 00:21:16,000 --> 00:21:19,200 Some will disappear by themselves in time, but some 390 00:21:19,200 --> 00:21:22,440 will stay there for a long time and will continue to over 391 00:21:22,440 --> 00:21:25,840 activate the complement system and possibly ongoing C3 392 00:21:25,840 --> 00:21:29,360 glamopathy. So I think, well, it's really an 393 00:21:29,360 --> 00:21:33,400 interesting decade which we are going into as clinicians and as 394 00:21:33,400 --> 00:21:35,920 patients, but promising, very promising. 395 00:21:36,120 --> 00:21:38,160 That's exciting. Even hearing you talk, it gets 396 00:21:38,160 --> 00:21:40,480 very exciting. So what I hear you say is for 397 00:21:40,480 --> 00:21:42,960 one thing that's going to be important is this idea of global 398 00:21:42,960 --> 00:21:46,560 teamwork, this idea of all of us collaborating to get the answers 399 00:21:46,560 --> 00:21:48,520 that we need. But also, I think you make a 400 00:21:48,520 --> 00:21:51,400 very good point of, you know, just surveillance of what 401 00:21:51,400 --> 00:21:53,360 happens and what do we need to do next. 402 00:21:53,360 --> 00:21:55,880 So those are all fantastic points, and I thank you very 403 00:21:55,880 --> 00:21:58,240 much for identifying all of those challenges. 404 00:21:58,560 --> 00:22:01,720 We are about to wrap up. So before we wrap up completely, 405 00:22:01,720 --> 00:22:04,360 Doctor Vandekar, I thought I would ask you very quickly, do 406 00:22:04,360 --> 00:22:06,880 you have any final messages that you want to share with us? 407 00:22:06,880 --> 00:22:09,040 Perhaps you've said most of them, but if you have a few that 408 00:22:09,040 --> 00:22:12,800 you'd like to add, please do. I think if you, those who are 409 00:22:12,800 --> 00:22:16,760 listening have patients with C3G in your practice and you're 410 00:22:16,760 --> 00:22:19,720 looking, clearly you're looking out for this new, promising new 411 00:22:19,720 --> 00:22:22,960 treatment options. But please try to contact your 412 00:22:22,960 --> 00:22:25,840 colleagues in expertise centre or reach out to other colleagues 413 00:22:25,840 --> 00:22:29,520 who treat CTJ patients and try to do it in a protocoled way, 414 00:22:29,560 --> 00:22:33,120 whatever protocol, but make one and stick to that or look for 415 00:22:33,120 --> 00:22:35,360 it. And then I think make sure that 416 00:22:35,360 --> 00:22:38,920 your patients is somewhere in a national, international database 417 00:22:39,200 --> 00:22:42,440 because we have to learn from now on how to use these 418 00:22:42,440 --> 00:22:44,800 treatments and this learning has just begun. 419 00:22:45,240 --> 00:22:46,600 Yeah, I think that's an excellent message. 420 00:22:46,600 --> 00:22:50,160 So thank you, Doctor Vandekar, for joining me for this session. 421 00:22:50,240 --> 00:22:53,640 It was really great having you here, and you clearly have a 422 00:22:53,640 --> 00:22:57,280 number of wonderful insights into what this new decade will 423 00:22:57,280 --> 00:22:59,640 look like for us. Thank you for joining us. 424 00:22:59,720 --> 00:23:01,880 Thank you, It was a pleasure. Thank you for having me. 425 00:23:02,360 --> 00:23:06,360 I'm Doctor Carla Nester, To access this and other episodes 426 00:23:06,360 --> 00:23:10,720 in our series, visit kdgo.org/podcast. 427 00:23:11,040 --> 00:23:12,120 Thank you for listening.