so as in closing out the professional track U we wanted to um um emphasize my time gy type 2 the foundation has a keen interest in trying to um stimulate more interest in my time distopy type two and that's what our last three presentations are going to deal with and the first one is from um Johanna haml um who will speak on disease severity and progression in dm2 all right so I'll get started again I will be speaking about our studies of disease progression in dm2 and to start off let's uh think about where we are um rapid advances are made in dm1 we heard a lot about it yesterday and today and from our patients and we can the the question is can we harness the momentum for therapeutic development in dm2 and following that question um it raises the concern what are the commonalities between dm1 and dm2 and what are the differences and how do we need to account for the differences and so following up on that I'm presenting here on our current efforts in clinical research to clear the path for Therapeutics in dm2 and our attempt to kind of answer those questions the first approach to shed light on the commonalities between dm1 and dm2 is utiliz is a study utilizing the National Registry of DM that's housed in Rochester and you may have seen data presented from the registry on dm1 uh because we have a lot of patients over 900 patients with dm1 enrolled um but we have also a decent amount of participants with dm2 and so this study included 222 participants with dm2 and the methods of the registry may be familiar to you but just as a reminder um the registry was founded in 2001 or or initiated in 2001 in Rochester and since then participants um have received annual mailings um with a survey that asks questions about their perceived disease bir so questions like have you started using an ankle brace have you started using a wheelchair has a pacemaker being placed Etc among other questions and so people return those mailings to us and we have created this data set that anyone who is interested and applies to use it can use for to answer their research questions and so when we looked at um the data set just recently it included um up to 17 years of longitudinal data from registry members and on average because not everyone returned their survey every single year on average the longitudinal followup uh was covering seven years and the range was large though so there are people that have just been in it for a year or returned their survey only um at one year and then there are people who have um returned every single survey over 17 years and all that data flew into this study now there are a little bit more more of women than men there were about 60% of women in this study and again 222 participants with dm2 now I will Orient you to these graphs because they will all look a little similar showing the um each Milestone um on the Y AIS you see the probability of using or meeting a milestone for example the probability of using a walker one is everyone uses a walker zero no one uses a walker and on the x-axis the Ag and you see that the the risk of needing um a walker increases with ag in the dashed line you see dm2 and the solid line you see dm1 and so what we learn from these graphs that by the way I also use in the clinic because participants you know newly diagnosed with dm2 ask me what can I expect what does this look like and um with an attempt to answer these questions these graphs can be helpful but what we see here for example is that the risk of developing uh the risk of using a wheel Walker at age 50 is about 10% in um in dm2 and it's it increases to about 28% at age 60 now moving on to wheelchair use again similar graph just showing the risk of using a wheelchair over time and with a with increasing Ag and here you see that about 133% of people uh with dm2 um have had the the need to use a wheelchair up to age 60 and then moving on to disability and this question in the registry is specific it's not just disability to to anything back pain work injury Etc no it asks about disability due to myotonic distrophy typee two and so what we see there is that up to age 40 um the risk of having to stop to work because of dm2 is about 10% and that is in a disease that generally speaking is considered to affect people at older age so there is substantial disability before the typical age of retirement and that's what the registry data here um taught us now going forward to other important Milestones um the use of non-invasive ventilation either for sleep apnea or for Respiratory muscle weakness again you see that the risk of using non-invasive ventilation is higher in dm1 than in dm2 but um the risk is uh also present for dm2 so for example at age 50 the risk of using non-invasive ventilation is about 12% and just as a limitation here we do not ask the question have you been prescribed non-invasive ventilation and you can't use it we ask are you using non-invasive ventilation so the people who should probably use it um ideally is probably higher than what's representative in represented in this graph now moving on to Pacemaker placement which again is an important milestone in a person's disease life um and uh when we look at again the risk of using a using a pacemaker is greater in dm1 but it is present also in dm2 and up to age 60 about 8 to 10% of people have a pacemaker placed cancer uh research has been done about the increased cancer risk in dm1 mostly in DM one but what we found here which was interesting is that there is actually statistically no difference between the risk the the reported risk of developing cancer um with increasing AG in in dm1 and dm2 so in both forms of the disease the risk of um having a diagnosis of cancer up to age 60 is about 24% now moving on to diabetes and you may have gotten used to look at this graph and see the solid line on top and the dash line on the bottom because generally speaking the risks are higher in dm1 but here you see that it's flipped around and that was something we um didn't know before but um the probability of developing diabetes is actually greater in dm2 compared to dm1 so for example um in at up to age 60 the risk of developing diabetes is about 24% in dm2 and that's important for for me in clinic to um educate um my patients as well but now the question is what are the mechanistic underpinnings for that and we don't know but um um possible hypothesis may be that the pattern of weakness may play a role where dm2 has pre preferentially affected proximal muscles that are larger um so if there's an issue with insulin resistance in those muscles that might have a greater impact on developing generally insulin resistance rather than the smaller muscles um maybe the um the fact that there's less atrophy generally speaking may play a role um or other tissues may be involved for example the liver tissue um hepatized maybe they have a different um pattern of insulin resistance or fat tissue or even insulin secreting tissue so for example the the pancreas um is is there difference in how these tissues are involved in dm2 compared to dm1 so conclusions are it is feasible to collect data on disease burden in dm2 over a relatively long interval using Registries and I would like to uh point out with that data that the impact of dm2 at older ages is still very considerable and um there is a decent amount of risk to use assistive devices such as a walker or a wheelchair and again the disability data is interesting because there is a risk of having to uh retire early or become disabled due to DM to uh before the the retire the typical retirement age um with relevant socioeconomic consequences um the higher risk of diabetes that I highlighted here is mechanic mechanistically interesting and um warrant further study with that I would like to transition to the second uh study uh which now I just uh kind of focused on a whole long uh interval of disease progression using the Reg and looking at important Milestones but now I would like to focus in on a natural history study that covers three years of um disease in a person's life and um this natural history study um called stab dm2 was our first step to obtain natural history study in dm2 and we were interested to look at what outcome measures are responsive to disease progression over those three years and also we were interested in whether the splicing biomarkers that have been developed for dm1 and are currently used in clinical trials in dm1 can be directly applied to dm2 or whether modifications are required and so um we also did muscle biopsies in our participants so what did the study look like we enrolled people um by the way it's still ongoing but enrollment has closed so we have completed the Baseline visits of four these subjects 33 have um completed their one-year followup and then 22 have completed their 20 their 36 months followup and we're still finishing up those those visits and we have 40 individuals again a little bit more females but fairly equal 57% are are females and the age was broad um the average age is 55 but we had subjects as young as 22 and as um old as 77 participate participate now here um and work closely with Kate ier on this project um we um here I'm highlighting the the strength and function assessments that are done in this study so manual muscle strength testing is done in the upper extremity and then the lower extremity and neck extensors and flexors and then um quantitive muscle strength assessments with qma or qmt are done upper also in the upper and lower extremities and I'm just highlighting this here because you see um you know you capture a lot more muscles with mmt than qm T um just the way these methods work and I would like to just explain how we combined those muscles in the analysis so we did a mmt score for the upper extremity including all of these and then we uh analyzed mmt of the lower extremity uh including all the proximal and distal muscles of the lower extremity and then um we have an mmt score of all muscles which then includes also the neck flexors and extensors other strength assessments were the six-minute walk test time to ascend and descend four steps time to stand up from a chair and time to transfers 30 feet here in this slide I would like to um uh show you data from mmt so manual muscle strength testing at Baseline of the dm2 uh cohort uh highlighting the we the muscles that are most commonly weak um which we uh discovered in our analysis and those muscles that are most commonly weak are neck flexion hip flexion hip abduction and shoulder abduction and on the x-axis here you see the proportions of people that are weak and in the colorcoded color coding you see um the this the grade of weakness and so red is red is a five so red means they have full strength and everything left to that means people were weak and the more you go to the left the we the lighter the colors the weaker they are so for example more than 20% of people had no anti-gravity strength in their neck flexion and then there were some people here that had no anti-gravity strength and their hip abduction um and because of that here um we developed a comp a proximal composite score in the analysis as well including those particular muscle groups which in the clinic just seem to be most affected and most severely affected and now I will go from the Bas Baseline data to um the the the data on um longitudinal followup over the 3 years here you see the change in the average mmt score so all muscles included um at 12 months and at 36 months so that just depicts the change and what we see is a statistically um significant progression of that score at three years but not at one year similarly here just looking at manual m strength testing of the lower extremity you see a change in progression at three years but not at one year and then highlighting the proximal composite score that I just talked about um that shows the strongest progression at three years um but again not at one year so and then the proximal composite score also shows a strong correlation with a lower extremity function index at Baseline what is the lower extremity function index it is a survey that people fill out on their own it's self-reported perception of um uh impact of weakness so they people are asked how about certain activities of daily living um that um involves the lower extremities and the score is 0 to 80 and um the higher the score the better the self-reported function and what you see here on the y- AIS is that the higher the self-reported function the greater um their strength on the proximal composite store which is quite strong with a Spearman correlation coefficient of 0.9 and then um the time to go 30 feet was um uh people progressed over um three years as well you see a little Trend here but that was not statistically significant at 12 U months and then um similarly here you see correlations at the Baseline data from the time to go 30 ft um uh to the uh qmt lower extremity and the mmt lower extremity scores and I just mentioned the qmt lower extremity strength data did not show progression in our study but again I highlighted before that the selection of muscles is limited for for qmt and doesn't capture really the the key muscles that we think are most affected in dm2 and then the lower extremity function index that I just talked about um shows uh progression at 3 years as well and here you see a drop as well but um it's not statistically significant at 12 months um and then the lower extremity function index correlates also with the mmt score of the lower extremity with a correlation coefficient of 08 and then even though I'm talking a lot about lower extremity uh function um uh the upper extremity function index um shows also progression at three years um not as much but notable and statistic statistically significant um at 3 years now I want to shift um and talk a little bit about the the trans cryptonic changes um because we collected muscle biopsies from the tbls anterior ta muscle um of most uh participants and this is work from Matt tenner um and what we are looking at here is the supplice events are listed down here and the patients are listed here and the patients are colorcoded we compared the patients with dm2 to patients with dm1 and so you see the dm1 patients highlighted in red here and the dm2 is in green and then you see healthy controls in blue and what you see is that the um transcriptomic changes in dm1 and dm2 are relatively concordant about 96% are are similar um the and they fall along a spectrum here of sever so the red um color coding here is the most severe uh splicing derangement and as it get lighter it's less severe and you see that they fall on the Spectrum here from top to bottom with DM one most severe on the top and then interspersed less affected DM 1's and the dm2 patients and then segregating from these healthy controls and the one there's one interpers here a mildly uh affected dm1 patient um but that uh that was the the trans cryptonic splicing analysis by Matt Tanner and so next slide I would like to highlight some of these compared comparing again dm1 dm2 but also comparing different muscles so to orient you here um so on the left so these are splice six uh uh selected splice events and it shows the percent spliced in and so right up here you see a healthy ta next to it you see the um percent suppli in for healthy quads a quadriceps muscle then you see um data from 172 um dm1 muscle biopsies of the TA then you see in green the dm2 TA data and then next to it dm2 quadriceps um data and what you see here is that they that dm1 and dm2 fall along the same spectrum of course there's more people with dm1 included here um but they both segregate uh from uh uh separate out nicely from the healthy controls um along those uh uh different spli events and also from this data um you don't see a huge difference between the TA and the quadriceps now um there is a disclosure here because um we did a biopsy from the TA and the quadriceps and um the issue is that these muscles are not preferentially affected in dm2 but they are in dm1 um and in fact in our study on mmt only 30% showed weakness in the TA or quadriceps in our dm2 participants so what is needed as a next step is to um biopsy and analyze uh preferentially affected muscles in dm2 and this is something we are working on so to conclude um disease progression in dm2 is slow but it can be measured um assessments of strength and function strongly correlate also with the um self perception of disease and function in particularly when we preferentially selected muscles that are um affected in dm2 with a proximal composit score the splicing analysis suggests that the tools already developed for dm1 can be applied to dm2 for example to demonstrate Target engagement um but we are doing further studies uh to uh look at preferentially affected muscles in dm2 and overall these studies support the the feasibility of measuring disease burden and and hopefully in the future drug effects in dm2 and with that I would like to close and thank Kate and Mike McDermot and the whole team at the University of Rochester and of course most of all I would like to thank all participants and their families for participation in this study and thank you for the opportunity to present it thank you for the great uh work uh I had a question uh your data did you stratify them by age uh for dm2 or also age from onset of symptoms or years from onset of symptoms because I think that matters when you when to say where they are with the disease or how old they are I think it would be helpful um you mean for the first part the Milestone second oh the second second by the way for the yeah I I can comment on that because exactly that's important and um by the way for for the first part for the Milestone uh data we did that too uh for dm2 looking at disease duration and age ofan set and that actually didn't U have an impact on the data it did for dm1 but uh not for dm2 um and in in the second part um we looked at that uh for disease duration um this is a preliminary analysis and it didn't seem to be statistically significant um but the numbers are are uh maybe too small so we have to look at that again when we have the full cohort thank you and second quick question did you look ask for autoimmune diseases in your part one presentation like for from patients any presence of autoimmune disease yeah yeah um we have that data um because it's comorbidities are collected in the registry as well as our medications that can give a clue um but we did not include that in this analysis yeah thank you very nice Johan I have a question about whether you have any insight into uh differences in repeat length in dm2 and dm1 and and whether there are different threshold lengths that are required to see these changes yeah um I think um you yeah it's it's obvious that the it's technically difficult in dm2 so nevertheless uh we did that analysis for the registry because we do have the repeat length on a decent amount of uh participants done by although this disclosure done by commercial Labs um and then it's entered into the registry so we um did an analysis whether repeat length um has an impact on any of those Milestones or outcomes and it did not in dm2 in dm1 of course there is a signal and I published that um but in in dm2 it did not but that's difficult because again I'm not so sure we can rely on the quality of those repeat lengths based in uh measured in commercial Labs but of course in the in the studies moving forward we are very interested in in looking at that including our biopsy studies quick question yeah great talk Johanna in terms of comparing dm1 and dm2 in progression if you do the the comparison is it is dm2 maybe two to threefold slower in terms of progression or just in terms of Park I was just trying to get a understanding of that um yeah it depends on on what you're looking at in terms of just muscle strength or the other outcomes I mean the the Milestones you know I kind of show it that it's the odds ratios are usually between two and three um uh comparing the two diseases and in terms of uh functional outcomes we would have to look at it but it's I would say two to three-fold makes makes sense that I think there's more of a signal in dm1 at year one of course um than we found in dm2 so it seems like the progression is slower yeah and just one followup to that in terms of we're lucky and or fortunate in dm1 to have the correlations with Miss splicing and functionality and maybe you published this and I've missed it but is there anything that you have good correlations with functionality and Mis splicing yet in dm2 so um the we analyzed the first 16 people biopsies of dm2 and we have more so that needs to be done still but in those first 16 um participants there was no correlation to strength in the TA um but um again that is limited by that the TA is only weak in about 30% so it's really not that helpful so that's why we need to do um that we need to cor correlate it with a muscle that's actually affected in most people um but again the other question could it still display I mean it could still be a mark of Target engagement so even if we don't have that uh thanks Johan it's really exciting I'm eager to see this move forward I was curious about the diabetes uh that you showed did you look at BMI was there a BMI difference between the the two populations um so good question the BMI is collected in in the registry but we didn't look at that um that's that's something we thought of because um again metabolic syndrome is a little more common in dm2 and um muscle wasting again isn't isn't as common and um and dysphasia isn't as yeah so that all makes sense that there might be less of a malnutrition issue but um that's something we we should look at in the in the future um definitely yeah um cataracts are highly prevalent in being to what about FS District do we know anything about that um so we don't I I don't have uh that data but I keep asking people um if they have folks Coral distopy so far I've only um encountered dm1 patients with it and then I had one family that um had folks but then I teased out the the pedigree and it came from the other side of the family so I think that person actually has a tcf4 mutation and it's not due to dm2 I didn't prove that but it's clearly in two two from two family trees so where the folks and the dm2 comes from but it looks like John may have yeah we have some families with dm2 and but we the same question it's just common yeah yeah yeah Pati to closely examine we we actually modified our study protocol and it's in there to look for fols but then the pandemic hit and so we we didn't look but we can y okay thank you