this program is brought to you by Emory University all right good morning everybody welcome to Friday morning conference our speaker this morning is uh as you can see Dr melroy de Souza one of our first year clinical tract fellows um melroy did his undergraduate studies at Lafayette College in Pennsylvania and in medical school at Robert Wood Johnson in New Jersey there's residency here at Emory was the chief resident at Emory University Hospital last year he is going to discuss a topic near and dear to my heart uh this morning hypertrophic cardiomopathy take it away Milroy okay thank you Dr Williams and uh thank you everybody for making time this morning to come here to my talk uh so yeah the topic today will be hypertrophic cardiomyopathy and we look at emerging therapies and promise for the future I have no disclosures so the objectives to the talk there's a lot to cover but we'll talk about the the pathophysiology of HCM and really highlight the phenotypic heterogeneity uh we'll talk about current management strategies with the guidelines but then also we'll end with ongoing clinical trials for new agents that are here the scope of this talk won't really talk about sort of Lifestyle management lifestyle warnings that we give to patients or indications for ICD as you'll see there's a lot to cover and those are good for another talk as well so we'll start off with three patient cases to really highlight the unique presentations all of this disease and then that'll be a segue to the rest of the talks so the first patient is 47 year old gentlemen he has an apical variant of HCM Osa hypertension uh this was actually picked up after a pre-operative screening of surgical screening with an EKG that we'll look at he was known to have an apical inferior septum that was 1.9 centimeters thick he had an elevated mid-cavitary gradient but not an lvot gradient and we'll talk about that distinction but because of this he was determined to be a non-obstructive heart of cardiomyopathy physiology he had progressively washing symptoms of heart failure he was not able to tolerate calcium channel blocker in the past and he can only tolerate a low-dose beta blocker now and he gets fatigued with higher doses so this was his for that screening EKG I talked about just the big takeaway is normal sinus rhythm and so you could pick out signs of LVH so that warranted him to get an echo and this was an echo more recently not right back in 2010 but as you can see um he has uh some thickening over the uh his intraventricular septum his posterior wall but as you get to that short axis View and look at the Apex yeah you can start to appreciate how thick um his Apex is um and his Apex is asymmetrically thick compared to the rest of the myocardium um this is um the Doppler signal looking at the peak pressure gradients or the mean pressure gradients but notably here this is the pressure gradients in the mid LV cavity and not in the lbot or the outflow track so because of that reason he's a non-obstructive physiology and here is just a strain pattern um LV strain pattern as you can see it's sort of this inverse amyloid characteristic pattern where you know M what we think about cherry on top but here um his biggest defect is in the Apex and surrounding septal regions which also goes into his apical predominant hypertrophic cardiometric phenotype so on follow-up recently the patient continues to have nyha class two and three symptoms mostly exertional dyspnea he's only able to tolerate low dose of Atenolol and he's tried other beta blockers and does not feel well with them he's frustrated understandably about his lack of options and is persistently poor symptoms um and for him you know we've discussed possible apocal myomectomy with um particularly at male one of the few centers that does it um or or an off-label enrollment in one of our clinical trials and we'll see why these are options for this patient later on our second patient um young gentleman 35 year old man history of HCM that was diagnosed at age 10. he was previously taken care of at Boston Children's has a has had all the complications of hypertrophic cardiomyopathy that will hit on a very sick person he has an ICD upgraded to a crtd and then now he's developed borderline dilated cardiomyopathy with RV dysfunction so really heading towards end-stage heart failure um this is actually a slide from Dr violin's Grand rounds that she gave but as you can see this patient primarily has um asymmetric septal hypertrophy I know now I mentioned that he sort of borderline dilated to his you know Echo parameters have changed over time but um earlier on as a disease course he did have um Ash as you can see here with this asymmetric hypertrophy this is his stream pattern you know compared that to the last patient who had Central sort of clearing around the Apex but this patient had sort of a extensive myocardium involvement of hypertrophic segments in his Apex is relatively spared um so this is sort of that gerontov do not be confused with you know thinking that this is an amyloid pattern this is somebody who's had kind of progressive hypertrophic disease sound that leads to the strain pattern and here's just a 3D rendering of this long axis view showing the receptor thickening okay so then this patient he's now that he has advanced heart failure uh we think about gold rectal therapies for him but unfortunately he cannot tolerate beta blocker cannot tolerate interest so the only medications that he's on right now is low-dose Lisinopril and evaporating um he has persistent nyha Class 2 symptoms um biggest driving symptoms fatigue and he is now established with the advanced heart failure gland had begun discussion for advanced therapy so again very sick gentleman and I presented two cases to you and I don't want to cause you to be sad and depressed about HCM early on a Friday morning so we'll wrap up with patient three who has some promise here um he's 67 history of hypertension mild as CAD SAS was PCA in 2018 who was diagnosed with a hypertrophic cardiomyopathy in 2021 his phenotype is the asymmetric septal hypertrophy with the max width of 1.8 centimeters seen on MRI on Echo was closer to two he developed fatigue and dyspnea while walking up his stairs in his house so he's coming into Clinic kind of complaining of nyha class three symptoms I found to have an lvot gradient of about 80 milligrams millimeters per Mercury post valve Salva so he needs criteria for obstruction his Holter was negative arrhythmia and he's initially treated with a beta blocker this this is a sort of an pictures from analogous patient um just that has a better echo images to show but really the clinical course is pretty simple so as you can sort of see here his interventricular septum appears I think in particularly compared to his posterior wall and then we see maybe that sort of described a little bit better on the short axis view on an end on the apical view as well and I understand that this is a bit harder to see but ultimately this his post vowel Salva pressure gradients in the lvot is as high as 162 millimeters per Mercury so very very high lvot gradients so you know this patient comes to Clinic he's having high gradients he's having very very bad symptoms so what can we do for him so just two months ago he was started on a novel myosin inhibitor and we'll talk about what that is later on two months ago and he comes in this month actually and he said that he's now able to play golf and he's able to walk around his house or around the neighborhood with minimal Destiny so his symptoms have gone from class three to class one in two months which is really incredible so that sort of just sets up the the way for the rest of our talk here um and then his follow-up Echo this was actually Done Yet two months after actually one month after his him starting on the novel myosin inhibitor and as you can see his myocardium Still Remains thick but his uh resting gradient and his post valve Salva gradient have um remarkably decreased more than by more than half after starting this therapy for just one month so now let's just talk about the disease um briefly the history and diagnosis of HCM so it was first described really not that long ago in 1957 by Dr Donald here in London who wrote about eight cases of asymmetric septum hypertrophy that he noticed on patients with autopsy that he didn't expect to have cardiac disease then a couple of years later doctors Morrow and bronwald also reported some findings of patients who were now undergoing open heart surgery and looking at gradients and hypertrophy in those patients and really what started to kick it off was um this case series also published by Dr braunwald in 1964 with 64 patients with a similar condition which at the time he called idiopathic hypertrophic sub aorticostenosis um so how do we Define hypertrophic cardiomyopathy um so it's it's really a morphologic expression of hypertrophy combined to the heart or confined to the heart um it shouldn't be other systemic manifestations because then you think about other disorders at play um and then you look at you know you get an echo and you think about this oh you notice this patient has lph and the absence of other cardiac disease right they don't have uh long-standing uncontrolled hypertension that could explain it they don't have a metabolic disorder a systemic disease such as sarcoid or amyloid or infiltrated process that's causing a thickened myocardium so you rule all that out and you notice this finding on Echo and you start to think about HCM so in terms of a criteria they need to have an end diastolic wall thickness of any LV segment over 15 millimeters or 1.5 centimeters however in patients who have a family history of this we have a sort of more stringent criteria so if they have a wall thickness of over 13 millimeters or 1.3 centimeters then they meet criteria for HCM now the big distinction once you've diagnosis p.m is to try to figure if this is non-obstructive versus obstructive because that has really a lot of weight in how you're managing these patients and also how you're thinking about these patients about their disease course because those who have obstruction have are sicker they have worse symptoms and they have worse prognosis so how do we Define obstruction so you need to have lvot obstruction as we highlighted the difference between case one and two if you remember so lvot gradient either at rest or on provocation of over 30 millimeters per Mercury meets criteria for obstruction so then the going to the pathophysiology of HCM it's primarily when patients have it it's a single gene mutation disorder but there are over 900 genes that have been identified in mutations that could lead to this overall phenotype um it's inherent in autosomal dominant pattern um and really you know this is a a nice cartoon but also kind of a scary cartoon with different components of the sarcomere but what we ultimately care about this is myosin this is a myosin binding head which ultimately binds to thin filaments of actin via these cross Bridges and I know there's I said there was over 900 mutations that are implicated but really the two most common ones are myosin binding protein C and betamycin heavy chain here vast majority of page I think up to 50 or 60 percent have one of these two mutations and ultimately what that does is that increases the number of cross bridging between actin and myosin which ultimately then leads to myocyte hypertrophy cell enlargements that hypertrophy will call cause this disarray and architecture and this disorganized pattern which will then lead to interstitial fibrosis and then on a macroscopic level lead to endocardial fibrosis which you know then we start to pick up on MRIs then we think about this causing um making patients prone to arrhythmia so this is sort of the um kind of progression of disease and why we get from hypertrophy to fibrosis in HCM in terms of phenotypes of HCM what we might see on Echo it's a it's a heterogeneous disease so this is a nice sort of figure on up to date actually that goes over several different phenotypes so here this is normal myocardium in B this is the one of the cases that or two of the case that we talked about with asymmetric septal hypertrophy or Ash C is this basal primarily basal septal hypertrophy or sigmoid septum that we see not infrequently Group D is this sort of mid-cabatory thickening which leads to the sublimitation of the mid LV cavity e is not a very popular a common phenotype this primarily lateral wall hypertrophy but it is possible I suppose G is an apical variant so apical variant HCM as you can see the Apex is very thick here making the overall cavity small and then some other variants here such as right ventricular hypertrophy is seen in eye and then an F is really sort of that dilated thinned out walls and and sort of end stage of presentation so you know what are our patients going to tell us what are clinical manifestations so by and large what we care about preventing and what we care about treating is symptoms of congestive heart failure and that primarily comes from a few different factors diastolic dysfunction from the stick and myocardium that has impaired relaxation it comes from lvot obstruction particularly when these patients are trying to exert themselves their obstruction gets worse because of increased sympathetic drive and increased inotropy these patients will develop mitral regurgitation you know either from long-standing diastolic dysfunction leading to Mr or we know of systolic anterior motion of the mitral valve that causes the substruction also tends to pull the leaflets apart and causing some Mr so that could make heart failure symptoms and then ultimately when these disease progresses particularly like in patient number two you can have systolic heart failure symptoms kind of at play which also plate these patients they might tell you about chest pain which will go into detail on the next slide they can complain about syncope you know we think about young young athletes who have HCM and and having either malignant arrhythmia or having syncope and the Syncopy comes on from a couple different mechanisms one is you know if you think about post-exercise lvot gradients are the worst and that's a probably a combination of things is decreased preload um really high inotropy really high sympathetic States so at the during and the end of exercise the LBT grade is the absolute highest so it makes patients at really high risk for developing syncope and then of course you know you also have comorbid malignant arrhythmias that come in with patients with HCM which can lead to syncope and then sudden cardiac death and atrial arrhythmia is particularly atrial fibrillation is also something that troubles these patients because of long-standing diastolic dysfunction Mr so on and so forth so where does chest pain come from so patients have particularly just HCM it's not really coronary stenosis as we think about for uh for angina and chest pain but it's really a microvascular issue which is uh comes into this imbalance between increased myocardial oxygen demand and reduced myocardial Option Supply essentially so there's an increased demand because these cells are big they're hungry they work really hard so there's an increased demand their increased wall stress and increased lbot obstruction gradient and this you know drive to increase ionotropy will increase myocardial demand however we don't have the supply to match that and why is there Supply reduced because if you just think about the hypertrophy and these cells getting bigger it makes for these smaller blood vessels it kind of makes their course much farther or much more difficult for blood and oxygen to Traverse the distance between the epicardium and The myocardium tends to increase with this interstitial fibrosis with these cells getting bigger so just physically there's a barrier for blood and option to get there inadequate time but then also there's comorbid endothelial dysfunction impaired vasodilation which then also leads to an impaired O2 Supply so the chest pain exertional chest pain is driven by this mismatch here and not quite by coronary disease but of course as we saw in patient number three he had coronary disease sort of before he was diagnosed with HCM so they're not mutually exclusive so how do you diagnose HCM really Imaging and really Echo is the way to go so echocardiography can help you establish diagnosis and which one of those patterns if you remember that up-to-date slide of pattern on hypertrophy the Doppler technology has gotten so good that we can actually use that to quantify the severity of gradients um and uh you know if you're if your rust Echo is sort of equivocal you're not getting good about solver readings then you can do a stress echo to really elicit how severe the gradients are you can look at the mitral valve look at the apparatus the presence of systolic anterior motion of the valve presence of Mr and then evaluate initially for diastolic dysfunction and then later disease look for a system function as well um just a couple sales I know I probably our videos were more instructive earlier on but um a couple still images of echocardiography you see here this anterior septal primarily involvement of the um of HCM and you have some thinking of the inferior posterior walls as well and you can see that on the two chamber apical View and then Additionally you know besides just looking at the walls and measuring the walls in 2D you have Doppler technology that helps you determine the your gradients such as here helps you determine diastolic function so it gives you echocardiography really for you know places that don't have a lot of resources but also have good resources like we do echocardiography is a really good test that tells you a whole lot about the disease um there's also MRI MRI for diagnosis is helpful if um you know you're thinking there's HCM and you really can't get good views of certain areas and those areas are the Apex posterior septum and anterolateral walls that sometimes you just can't get really good resolution on an echo um but your Association is high you can follow that up with MRI to really confirm okay do I have hypertrophy in these segments further than that it helps with prognosis by determining extent of myocardial fibrosis because we know more fibrosis increases the risk for heart failure symptoms and certainly increases the risk for ventricular arrhythmias and then for patients who need septal reduction therapy which will describe what that means later on it's great for pre-prestedural planning look at the anatomy before kind of deciding the procedural course um some examples of MRI here so this patient has asymmetric septal hypertrophy which I think you can see really nicely here in the apical View and in this short axis view here and then in D and E it's really describing that late gatolinian enhancement which indicates um you know High degree of fibrosis um in these areas here um so you know MRI can give you a lot of Diagnostic and prognostic information as well so it's a helpful tool to have and then there's catheterization you know it's not really in the armamentarium for diagnosis any longer but you know if you're not able to get good gradients um on an echo over the patient's getting a catheterization for other reasons there are some things that we can find on catheter um so you know particularly when we're when we're in there it's helpful to do provocative Maneuvers so on the table the patient can do about Salva under the drape they can do upper or lower extremity exercises to again increase inotropy and try to elicit that gradient you can induce PVCs and there's a cool finding that we'll talk about in the next slide or you can give them isoprotein and all infusions and here's some tracings um aortic and LV tracings that help you kind of just determine okay I noticed some pressure gradients across the aortic valve because this would be from as or could this be from a dynamic obstruction like hypertrophic cardiomyopathy so on the on the left here you see um sort of the findings in something like severe as so you have a fixed obstructive defect you have sort of you know uniform filling of the aorta across the aortic valve and really you have this late peaking pressure on in the aortic valve at the very end of systole which this actually represents severe as whereas in a dynamic obstruction like in HCM what you see is this very rapid early filling um across the aortic valve into the aorta and then you have sort of because the lvot obstruction gets really bad and sort of mid to late systole you have almost you know cessation of flow across the aortic valve so that's what you see here that very rapid increase of filling across the valve and then not too much else after that that happens in early system that makes you think about a dynamic obstruction then you know what you can also see and I was fortunate to see this in the cath lab too is that broken bra brawnwold Morrow sign or just for sure called a broken bra sign what it is it's this post PVC augmentation of systolic pressure in the LV which then really makes your gradient worse so this is the tracing Peak to Peak between the LV and the aortic and in the aorta sorry and maybe they have a resting gradient around 30 here so sort of borderline for obstruction and then the patient has a PVC uh there's a you know a physiologic pause increase in diastolic filling time but also an increase in inotropy which is physiologic phenomenon and then the next sort of beat the your LV systolic augmentation pressure just goes way up but then that increase in iotropy really um increases your lbot obstruction which then decreases your pulse pressure in the aorta itself so you see not only like a widening of the gradient but you see the aortic pressure get lower the LV pressure go way high and that only happens really with this lvot obstruction and HCM so that can be helpful but again catheterization is not you know needed for diagnosis of this condition so the rest of the talk um after a little bit of background was spent on medical management current guidelines and new therapies um so traditional therapies beta blockers calcium channel blockers and exoperamide so beta blockers are first line um they are nice because they can be used in patients with or without lvot obstruction same thing with calcium channel blockers however you know they improve patient symptoms the goal is to decrease inotropy increase diastolic filling time to help patients symptoms but it doesn't do anything for disease course okay and as you see patients are young with this disease patients have intolerance to beta blockers you have intolerance to calcium channel blockers we saw some of those with our patients that we started off the talk with so there are these therapies but they're either not really well tolerated you cannot increase their doses a lot or patients you know just don't have a lot of success on them and then if you've given a trial of beta blockers calcium channel blockers or both really and the patients are still having persistent symptoms um the guidelines say it's reasonable to add isoperamide as a reminder it's a 1A class 1a antiarrhythmic primarily you know for this disease works as a negative inotrope and and in opposition to beta blockers the calcium channel blockers it is shown to decrease rest lvot gradients um the first two do not but it is an antiarhmic primarily works on the IKR channels so you are at risk for QTC prolongation so patients have had sort of middle arrhythmias before torsades before are you really limited and you cannot use disoperamide and we'll go over the guidelines but the other therapy then once patients are on these medications are still having class two to three symptoms The Next Step would be surgical myomectomy which is a surgical approach to anatomy-based approach versus alcohol septal ablation which is a catheter derived procedure for really reduction of that hypertrophy and Mass so these are the 2020 Acca guidelines for Holcomb so patients with hypertrophic cardiomyopathy with demonstrated obstruction um so if they're sort of in the class one area where they're not really having any symptoms it's reasonable to have them follow up and not have them start on any therapies but when they developed class two symptoms that's when probably the first medicine you're grabbing for first class is the beta blockers um and then you know you can they're not tolerating switch to calcium channel blockers keep them on a low dose beta blocker and add a calcium channel blocker if their heart rate and blood pressure tolerate it and I didn't mention this on the other side but we do non-dihydropyridine calcium channel blockers so they're Alpha Medical and deltaizen and so symptoms persist then you can add asopyamide or you know start to think about septal reduction therapy if they are not a surgical candidate you do a catheter-based septal ablation but if they're a safe a reasonably safe surgical candidate then you think about myomectomy um these are right from the guidelines for HCM without obstruction um and I didn't post the exact guidelines for obstruction but I will tell you that the what's available for non-instruction is so much less than for obstruction so um really the the best indication is okay for patients who start to develop symptoms they have a preserved EF start to develop symptoms um you can add beta blockers or calcium channel blockers for them but everything else is a you know it's a it's a suggestion and it's reasonable to use but the the evidence for it's not great so since um patients with non-obstructive disease don't have that lbot obstruction they're not as dependent on maintaining a good preload it's reasonable if they look like they have volume on them to use low-dose oral diuretics but again you have to be very careful with diuretics in these patients um some you know even weaker evidence to try to use arbs or race Inhibitors and then this is sort of interesting if you remember in patient one who had non-obstructive um uh phenotype he's having bad disease we were thinking about referring him for apical myomectomy um so that's what this this part of the guideline is saying and highly selected patients um but also in a very highly selected number of centers um thinking about something like apical myomectomy could be a reasonable option but there's sort of a lot of caveats um and again the evidence for this is not great that's there so uh what is septal reduction therapy um so as I said there's sort of two flavors surgery versus catheter based um the guidelines you know do talk about septal production therapy as being a good option but it really is with the caveat that it has to be done at a center of excellence um so that's just Emory fortunately we are one and there's a handful of centers around the country um but this really is based on uh volumes the operator volumes operator comfort with these procedures both surgically and um on the Interventional side so they just can't be done any by any hospital and uh you know we had this a similar discussion like this igrady and the attendance we're talking about really bad out seeing really bad outcomes for patients who've had these procedures not at Center centers of excellence so you know if you're not in your center of excellence the patient doesn't have access this is probably off the table but for those who have access to you know our sites or different sites around the country my surgical receptor reduction therapy is a good option Surgical improves gradients and then by improving gradients you're improving systolic anterior motion of the valve and then also you're improving same-mediated Mr so you know patients do have decent outcomes after this alcohol ablation is sort of head-to-head you know a little bit worse than a surgical myomectomy but still does well for patients but it becomes less effective when the gradients are really high or when the wall thickness is really great too over three centimeters typically it's important to note though SRT it's sort of like debulks in a way but it doesn't alter the disease core so patients can still are at risk for developing heart failure or Advanced heart failure developing afib so you know once patients are there it's it's not like they have a Curative therapy this is sort of just a measure to try to help them out but it's not slam dunk so the treatment summary of what we have so far and what's in the latest edition of the guidelines um medical treatment is is um is there but in in clinically it's not often well tolerated you're not able to get a lot of efficacy because you can't sort of um increase up titrated doses as much as you might want to um receptor reduction Therapy is mostly reserved for obstructive phenotypes but as we saw this may be an option of non-obstructive but but primarily is restricted to centers of excellence so many patients like patients one and two are like caught in the middle without good options without with end-stage disease um so you know up till this point there was no FDA approved treatment for HCM so you know there's a big need in this field so then that kind of sets the story well for mavic Hampton which is the new kid on the Block um so what is mavic Hampton um it's an allostatic selective and reversible inhibitor of cardiac myosin atpase that's like a biochemistry word soup which we can break it down so allosteric basically just means a molecule that binds to a particular binding site and changes the action of a protein and the protein that is of Interest here is myosin ATP Ace this myosin actin cross bridging is an energy dependent process driven by ATP so what myosin does is it binds these ATP Aces doesn't let that energy conversion happen so over time with HCM they have increased cross bridges over time we see a decrease in the number of cross bridges in patients with these novel myosin inhibitor and the other I think probably the most important word in this phrase is reversible and we'll talk about why the reversibility is a very key component of this drug overall it promotes relaxation and decreases ldot obstruction Half-Life about eight days good oral bioavailability and mostly linearly excreted so um now we'll go through a series of trials that really brought mavic Hampton to to fame and then ultimately to FDA approval so the first one was Pioneer HCM about 2018 um the study was reported it's a small phase two trial again phase two trials are just saying you know does this medication work and the way that we think it's going to work and then are there doses that are effective and safe for patients so before a large trials phase two trials could try to answer those questions they're usually small as you can see this trial has only 21 participants they were split up into two groups one group had higher doses of mavic Hampton without other therapy another group had lower doses of mavicampton and continuation of their Baseline therapy calcium channel blockers beta blockers they usually don't combine mavicampton and disappear in mind the primary endpoint here is looking in a change in post-exercise pressure gradient from Baseline and then some secondary endpoints they looked at just did the the gradients go down under an absolute value of 30 was there a change in the patient reported distance score are changing pvo2 Max which is really surrogate for Exercise capacity resting in valsalva gradients EF and the the drug reversibility effect that goes into you know safety and also just um reversibility of any adverse effects that might come on and then some exploratory endpoints changes in nyha class the Kansas City cardiomyopathy questionnaire which is really you know with cardiomyopathy the patients take this question in different domains higher the score meaning less severe their symptoms mean they're doing better so higher scores are good and then NT probe and P which is really a surrogate for anything about wall stress so a lot of numbers and data on the slide a summary of the results of pioneer so their primary endpoint looking at the post-exercise lvot gradient so cohort a again was the higher dose mavicampton group cohort B was a lower dose group and as you can see um the map the higher dose group had also a higher change or decrease in Baseline of their lbot gradients the lower dose group also had an improvement but not quite to the magnitude that the high dose group did now um the thing to really catch your eye in terms of adverse effects is that the higher dose group also had a greater decrease in their lvef um as a mean compared to a lower dose group and we'll we'll talk about that with further trials and we'll assess that sort of scary finding there and then the median change in NT probe BNP really kind of a surrogate of wall stress we can see that the higher dose mavicant group had a greater decrease in their BNP compared to the lower dose group and the other variables you know there's not sort of appreciable differences but again it's a very small study so we wouldn't expect to see really great effect sizes in all of our variables but sort of the takeaway okay we know that matter Captain does what we think it's going to do is relieve obstruction okay we think that it by doing that it's relieving wall stress but because it's a negative isotope uh it's doing what we might worry about is decreasing ldef so let's but it seems um the overall takeaways is just plasma concentration dependent um decrease in lvot gradient so higher plasma concentration greater decrease in lvot gradient higher plasma concentration and greater Improvement in VO2 max I didn't highlight this but you know the higher dose group had a greater increase in their VO2 Peak VO2 which is um you know actually size capacity compared to the lower dose groups so we think that the higher plasma concentration the better improvements they get but then also the higher plasma concentration seems to be a greater reduction in lvef so that's the um the balance that we have to strike here the nice part here this is where that reversibility comes in all of these changes the benefits and the harm were reversible after four weeks of stopping that Camden okay so and then with that the author reported that they found that sweet spot that therapeutic window between getting the benefits of a relief of obstruction but then also not dropping patients EF so once they found that good therapeutic window then that really opened the door for the clinical trial of Explorer HCM which is probably the most notable trial um to date in HCM so this was a phase three trial multi-center double-blinded Placebo control trial and patients wore on beta blockers or calcium channels at Baseline they could continue it but they were not allowed to be on disappear mind um the starting dose was five milligrams and there was an up titration at Weeks eight and fourteen so the um the criteria for up titration is um they would bring the patients in look at their plasma levels make sure they were in this therapeutic window um do an echo and do um basically another assessment of their gradients if they were within this um sort of within this range they didn't drop their EF but their gradients hadn't improved then that would sort of my meat criteria to increase the dose 5 7.5 10 15 sort of the intervals but if they started to drop their EF they would you know either you know drop the dose of the drug or stop the drug or um so the EF changes were really helping dictate the changes in dose the duration of the trial was 30 weeks and now with 251 participants again not a not a large trial but things that we like to look at typically but still much larger in this in the realm of hypertrophic cardiomyopathy and then their uh primary endpoint was sort of this either or so either patients had a 1.5 mils per kig per minute increase in their pv02 along with an improvement in their nyha functional class or they had an even greater Improvement in their pv02 at 3.0 and at least their nyha class didn't get worse so if patients met either one of these criteria then they were noted as meeting the primary endpoint so they had some improvement in extras capacity they had symptomatic Improvement in functional class okay they met the criteria or they had a much greater Improvement in their Express capacity and at least their class wasn't getting worse those patients met the primary endpoint and then the secondary endpoint was sort of more you know changes in these variables post exercise lbot gradient pvo2 myha class the Kansas City questionnaire and these are variables that we'll see in all of our trials basically so um this table um is really kind of the Hallmark summary result table in Maverick and really in HCL sorry in Explorer and HCM so far so um for that primary endpoint of um you know how many patients in each group The mavic Hampton group in the placebo group met that primary endpoint um for that either or criteria 37 of patients in the mavic Hampton Coopers only 17 percent of patients in the placebo group met that endpoint this was a significant change and significant difference now breaking down that endpoint and seeing okay like which one of these criteria did people actually get credit for like which one do they need so mostly it's patients who met that 1.5 increase in pvo2 with a change in Improvement in the mha class so most of them did meet criteria because of that but still you know patients um 25 percent of participants in the in the mavic Hampton group made that more more modest jump in their pbo2 and then you know some patients met all of the criteria in the uh in this primary endpoint with both a really big deep increase in their pbo2 and an improvement in the NY Chase score so 20 of patients met both versus only eight in the placebo group then now looking at the actual changes from Baseline of these variables so they're post lvot post exercise lvot gradients um the mavic Hampton group had a much bigger decrease in their lvot gradients compared to the placebo group and you know this is going to I'm going to be a broken record for the next several slides but these are all significant findings um they're improvements in pvo2 that we've seen the mavic Hampton group 65 percent of patients in the mavicampton group had an improvement in their Maha class versus only 31 in the placebo group changes in Baseline in the Kansas City question and again higher the score the better so mavic Hampton group had a greater increase in their score compared to Baseline compared to the placebo group and then this is sort of a patient reported dyspnea questionnaire and you can see at least their severity of dyspnea per answers is is better in the mavic Hampton group so a couple there are several plots in the Explorer trial but I just wanted to highlight a couple here um just to Warrant you blue is mavicampton group and red is placebo group and we can see you know the changes for in EF which is what we of course are drawing our attention um is you know fairly minimal between the mavicampton and the placebo group most of the times you know patients are starting with an EF over 70 it's one of the inclusion criteria but the mavic campaign group didn't quite decrease as a mean based on the EF and that was kind of held throughout all 30 weeks of the study but then look at each of these improvements on this is looking at the resting lvot gradients in the mavic Hampton group versus placebo and right at that first visit you're seeing such a significant Improvement in lvot ingredients compared to Placebo and this effect not only continues but if not gets a little bit better as time goes on and similarly looking at NT Pro BMP looking at wall stress the the mavic Hampton group Maybe started off a little bit higher probably not significantly higher but still higher than the placebo group and and right again at that four week checkup the the BMP levels are just so much better compared to Placebo so these results are dramatic but also very promising and very exciting because we don't quite see this effect this quickly in many medications this is a nice kind of colorful graphic to elicit the changes in nyha functional class between the mavicampton placebo group so if you just have an imaginary line down here towards the left is the mavic Hampton group towards the rightest placebo group and you can see you know at Baseline all patients were either NYC class two or three in both groups but at 14 weeks now some patients have improved to be NYC class one and then mostly our nyha class 2 and very small amounts of them are solar nyha class 3 as opposed to you know 28 being that way on the start then we come to week 30 and that effect continues so even more patients now are meeting nyha class one still a modest amount in my state class two and you know the class three goes up here but I just think like more patients were actually recording their nyha class score compared to here so I think that's why the numbers in the class three are higher in this last group whereas in Placebo you know you have some improvements in patients but not quite to the level of the mavic Hampton group so this just highlights also patients functional status are getting better now for the things that you know again draw our attention is that drop in EF so seven patients um in the mavic cancer group throughout the study and two patients um in the placebo group had an EF drop below 50 um most patients um in the mavic campaign group so seven out of oh sorry six out of seven had full recovery in their EF after eight weeks of not being on the medicine um and then one patient did have a drop in their EF and that was noted to be a complication of an aphablation but they still had some recovery of their EF after the washout period of mavic Hampton um and then one thing we haven't talked about as a variable yet is a change in LV Mass so uh you know sort of doing that not septal reduction but doing reduction therapy with this medicine essentially so the mavicampton group they had a decrease in their LLP Mass which was much greater compared to the placebo group too so um you know kind of a lot of variables being effective positively by mavicampton so uh you know the Explorer trial was it was was really a seminal trial in this to gain um good traction for mavicampton um for the efficacy particularly and you know sort of somewhat comments on their safety and then Valor um was uh sort of presented earlier this year and what Valor was saying is that patients who are probably the sickest in this population so patients who are on what we have is guideline medical therapy right now they're not tolerating it their symptoms are still class two or three and they're so sick that they actually per guidelines would meet criteria for supper reduction now before we send them to septal reduction can we instead put these patients on mavicampton and see if they still need such a reduction okay so they're probably so the primary so the inclusion criteria for all these patients in this trial where they all met criteria per guidelines perceptive reduction therapy all sick patients then the primary endpoint is at the end of the study period at the end of 16 weeks do they still meet criteria for supper reduction because if they don't that means that they're getting better primarily from mavic Hampton or if they still do um okay so maybe mavicampton is not as as great as we thought based on the Explorer trial and then the secondary endpoints it's the same variables that we've been talking about um in the Explorer trial so we'll kind of see if those results are able to replicate in this study here so uh thanks to uh Josh draw your attention to so this primary efficacy composite point just again saying at the end of the trial do these patients still meet criteria for subtle reduction um the mavic Hampton group only 18 of patients still make criteria versus 70 almost 77 in the placebo group I will like to take off take out these two patients in each group who opted for septal reduction therapy anyway so really the denominator does not include these patients so we'll look at sort of the SRT eligible based on guideline criteria we'll look at this box here so um even less patients so even a small proportion 14 of patients the mavicampton group versus 70 of patients in the placebo group met criteria for septal reduction therapy at the end of the study so this is saying that hey you know the intervention of mavic Hampton can you know allow a patient to get better without several reduction therapy without needing surgery without needing access to a center of excellence so this medication actually can help patients but also prevent sort of you know disease progression hopefully in a whole bunch of patients that did not have these options before and then uh you know not just sort of belabor the points but I'm sure you probably have taken a look at these numbers um all these improvements from Baseline and the mavic Hampton group compared to the placebo group are similar to Maverick someone similar to Pioneer where you see improvements just dramatic improvements in the mavic Hampton group compared to Baseline and compared to placebo so uh you know we sort of sounding like the salesman and I'm telling you about all these great things at mavic Hampton uh but let's get back to the EF right I'm sure that's on everybody's mind well we're dropping patients EF aren't we doing them significant harm so let's talk about that so um you know in each of these studies a few participants in each study did develop a drop in their EF um nine total patients explorers I know I said seven during the Tron there was two sort of in a post-trial analysis that developed a drop in their EF or under 50 and two patients in Valor um had a drop in their EF as well in Explorer they did say you know the mean EF of the patients who did drop was um still around 48 so you know not quite as low as the 30s and 40s but under 50 anyway they were all noted to have recovery EF all except that one patient with the afibrillation after the Washington period they all had an improvement back in their AF EF over 50 but basically back to Baseline um so you know as Pioneer noted there is a dose EF reduction relationship um but luckily this effect is reversible for patients who develop that reduction and again it's not most patients it's a very small amount of patients of each group so then um sort of the moral of the story in the spring of this year mavic Hampton did get FDA approval for the treatment of obstructive cardiomyopathy in patients with nyha2 to class two to three symptoms but you know that have to be on some guideline directed therapy prior to that there's some approved doses here and similar to the trials the recommendation is to start on a lower dose typically five milligrams and then have serial follow-ups to make sure their gradients are improving but also to make sure their EF is not worsening and if you know the gradient's not improving and the EF is okay you can increase the dose of mavic Hampton expensive medication here I would love to you know at the end hear Dr Williams and Dr byland's experience on prescribing these medications obtaining these medications for patients but at least from what I could see it's really expensive medication um what Oakley patients who have good insurance meet their deductible after a month or so can have most of this covered but you know the sort of the black box is the you know advised not to start in patients who have a baseline EF under 50 percent but if their EF is okay and you start this medicine they need serial monitoring probably every couple of months or so to start and then stretching it out just every six to 12 months of the Echo and looking at their EF to see if they're dropping their DF and then quickly wrapping up with some future directions so there's mava LTE study which is taking the cohorts from the Explorer trial and and watching them for five years to say okay the do these effects these great effects still um remain in five years and then also what is the safety of this drug in five years so as we as time goes on we'll get more and more information hopefully get more and more Comfort uh in prescribing this medicines then there's Maverick HCM so this is for non-obstructive HCM so our very first patient who had non-infective disease but really severe symptoms um really this was not studied in the prior trials that I talked about so this is a phase two trial participants could remain on their therapies they split them up into three groups low plasma levels High plasma levels and Placebo and the primary endpoint was that same sort of either or endpoint um that uh Maverick oh sorry that Explorer had so uh the mavic Hampton group um here again very small study but the mavic Hampton group had an improvement in their biomarkers so looking at NT Pro BMP the red is the higher dose the blue is a lower dose and the dashed line is a placebo so we can see that there's this dose relationship again with a drop in BNP um with mavicampton there's also an improvement entroponin level so this in this plot they actually combine both mavic Hampton groups into one plot and compared it a placebo and we can see that um you know for the for later on intervals there is a significant decrease in um interoponin interestingly you know there was no difference in functional endpoints so the there was no difference in that primary endpoint in this study between the placebo and the mavicampton groups and then they also looked at echocardiographic endpoints because you know in the attractive group you can use lvot gradients as your as one of your variables so they use um you know evaluations of diastolic function um in the used assessed with ede prime ratios and E Prime velocities and there was no difference when they compare to the groups however when they sort of did a sub analysis and looked at the the most sick patients in each group so the patients or the participants who had troponin levels over 99th percentile or Eda ratios over 14 in those patients they actually did find an improvement in the mavic Hampton group so 33 of the patients in the matacampton group and zero percent of patients in the placebo group met the primary endpoint so you know small study phase two just again looking to see if the drug works and is safe doesn't show sort of that that primary endpoint benefit I face value but when they sort of dug deeper for patients who are sicker mavicampton did sort of come out ahead compared to placebo and then the newest new kit on the Block is africampton this is a drug developed by cytokinetics again similar novel cardiac myosin inhibitor similar to matacampton this drug though has a shorter Half-Life than mavicampton and that becomes important because you know it gets patients therapeutic and some help sooner but also if you have that drop in EF you stop it and it's going to wash out a lot sooner than mavicampton so um that's that's helpful and then dosing is comparable to mavicampton starting at five milligrams the phase two trials has a really Redwood and then Redwood Ole is the extension study I'm not going to spend too much time on this but similar to Pioneer looking at sort of these outcomes in the phase 2 trial and then you know this is things are not published but these findings are coming out but starting at two weeks on the lvot gradients in africampton decrease in the treatment group 61 of patients improve by in what one nyha class and 17 actually improved by two classes there's an improvement in biomarkers at least at 24 weeks there was no drop an EF under 50 nobody had that so you know some promising data there and then all domains of the Kansas City questionnaire are going up and then that leaves the Sequoia a lot of sort of just California Drive driven trees I think cytokinetics is based in California but uh Sukhoi HCM now this is the sort of parallel to explore ACM and mavicampton this is at the Hampton um it's a phase three trial so this is a multi-center placebo control trial looking at similar outcomes compared to the avocampton studies there's a goal of being you know the largest HCM trial with the goal in Norm of 27 270 participants and excitingly Emory is one of the participating centers so if you have patients that have HCM certainly you know talk to Dr bylin Dr Williams about enrolling patients in the africampton study here and then you know possibilities outside of ACM uh just you know this this kind of thinking and spitballing would love other folks thoughts too is you know LVH and hypertensive heart disease it's certainly a different uh molecular um pathophysiology and development but you know with um these Inhibitors being uh primarily driven by inertrophy and increased relaxation wondering if this will ever sort of be applied to those disease phenotypes and then diastolic heart failure in general from a variety of underlying etiologies one of these Inhibitors will um uh be tested in those patients as well so just wrapping up with takeaways of you know treating patients with HCM and thinking about the at least guidelines that we currently have um use the echo echo echo echo and then stress that goes as needed to determine presence of obstruction if your diagnosis is sort of unclear think about using Mr in terms of medications the guidelines say you know grab your beta blockers grab the non-dihydropyridine calcium channel blockers first if they have obstructive phenotype and they're still not doing doing well think about disappear mind if they don't have other contraindications and then that they still have Persistence of class two to three symptoms consider septal reduction therapy if you have access or if you're at a center of excellence which fortunately we are here at Emory and then now you know hasn't made its way to the guidelines yet because this is you know just coming out but um we do luckily have an FDA approved medicine now called mavicampton we might have another one in the next coming years in africampton which are showing really great benefits for patients so glad to have these medications and help altering disease course and then if you started though please monitor their their Echo serially to make sure that they don't drop their EF um a couple really big thank yous Dr barlin uh was my coach throughout this you not only so knowledgeable on this topic but it's just such a great advocate for us as trainees um and really an inspiration and a big encouragement to all so thank you Dr bylin for supporting me through this um and you know a much better talk than I gave um is her grand rounds on YouTube so if you just look up hypertrophic cardiomyopathy historian Evolution um she gave wonderful Grand rounds in 2021 and Dr Robbie Williams thank you for leading our hypertrophic cardiomyopathy program thank you for leading our fellowship um and then most importantly thank you to my wife my pup for the last seven weeks I've not had any responsibilities as a home as I put together this talk so thank you to her as well um and uh finally I'll stop talking um and I guess we can ask any questions or if you have any compliments you can pass it along to well melroy I'll start with a compliment that was an excellent review uh and and thank you so much for that obviously it's an exciting time in the treatment of patients with hypertrophic cardiomopathy after many years of sort of beating our head against the wall in terms of medical therapy uh like you said it's been a it's been an exciting past six months or so um for us there are a couple questions in the comments I guess I'll start there and then we can open it up um to the group I'm sure there's a lot to talk about so if Yoma asked melroy any trial exploring use of mavic Kempton earlier for patients and prophylactic prevention of hypertrophy in patients who are genotype positive but phenotype negative have you come across any of that data so I know at least in um looking at beta blockers calcium channel blockers the guidelines say if patients don't have manifestations of heart failure or limitations you probably don't they would recommend again starting those therapies prophylactically um I don't know if for mavic Hampton if they've tried for patients who've developed this phenotype but don't have symptoms yet oh sorry have not developed the phenotype but are genotype positive I don't think that's been assessed yet um no not in my knowledge I mean I think this is a theoretical benefit down the line I mean there was a sub study of Explorer looking get MRI data and there was some LV Mass regression in patients on mavicampton so there's this thought that actually does have phenotype altering properties um so maybe this was this is a down the road thing but to my knowledge and correct me Dr piling if I'm wrong but um not no ongoing studies to my knowledge but I think this is a potential theoretical benefit of this class of medications down the road yeah that's correct there's no data uh congratulations Melrose by the way wonderful job exactly uh Steve Linderman asked how often would you do the serial Echoes on pages of mavicampton once a month for the first three months Steve it's it's required for them to get them they're in a rem safety protocol so we have to do an echo on them every month assess their EF and their gradients uh limited Echo but so 30 60 90 days and then another one at six six months then every six months after that so they these folks get have to get a lot of Echoes um and and where EF drops happening early versus late on single dose in my experience the EF drops are modest and they're pretty immediate um again Ozil correctly if you've had a different experience I've had one patient who had a dramatic EF drop like a 30 point EF drop but he went into afib with rvr um and he actually felt fine he came in for his Echoes like I feel great and his EF had gone from you know 6 60 to 25 or something and he felt great but we had to stop his mavic Hampton because he was also in he had a history he had known peroxism life Heaven had gone into afib so and this is a thing that others have mentioned this is sort of a new like that somehow tachycardia and mavicamson so afib and tachycardia and mavicamp and seem to be not a great mix um and then Dr lines yes dice Superior miter mavic Camden after beta blocker or trial which one first so I mean I think technically still dysopiramide would be your second line therapy um just because of cost and convenience you know relative to mavicampton um but at least we now have another option of dicapiramide is not tolerated or they don't get great symptom reduction so again awesome feel free to chime in if you have any other thoughts on those questions I agree I think one important thing to remember is this this mitigation is a negative financial trouble it's how the medication works so we do expect to see a modest drop in the ear about five to six percent and that typically takes about a month so but there are going to be some patients who are going to be quick responders kind of profound responders and those patients might have an earlier drop of the yet and they could have a more profound drop as well I think it is important to have the right clinical support staff in your clinic somebody who could be available to reach out to patients ask about their symptoms um maybe you could have your clinical staff give them a call in two weeks or so and make sure that they're feeling well but in most of the patients and this was shown in the trials as well it'll take about a month before they drop their AF and uh helps in children's and their symptoms as well yeah I mean it's it's a it's a good point it's not really toxicity it's sort of the expected effect of the drug and anecdotally I mean I've been the the the clinical responses drug for most patients is is quite dramatic is has been alluded to earlier in the talk they seem to really respond well mon has a question mon um that was an amazing talk I learned a ton um I have actually three questions um the first question is a logistic one and that is how do you adjust medical therapy when you start this mavic content maybe um uh the second the second um question is can you predict response based on mutation um and the third question is what would be the mechanism by which these medications would help diastolic dysfunction diastolic heart failure in the absence of hypertrophic cardiomyopathy no Roy you want to take any of those um yeah so at least that last last one how does it help sort of diastology um I think by by working as a negative inotrope by you know causing uh less cross bridging of mice in an actin that helps kind of alleviate that hypertrophy which and then as we see that also ends up with a decrease in LV Mass so I think by the negative anatropy sort of decrease in LV size and LV mass will help the relaxation component of the you know the diastolics so I think that's primarily how um that this can improve diastolic function um the question about the you know are some genotypes maybe you will be more responsive to this I don't I'm not aware of that at least so far I don't know if they've assessed this I don't know if they've assessed this sort of in in animal studies but I think you know a lot of the patients in this trial have probably a varied amounts of genotypes and seem to have good impacts on their phenotypes with this medication so I don't I don't know if there are sort of more like genotypes that are more responsive um to this medication or not um and then I forgot your third question Dr Joker sorry adjusting the dose I mean go ahead yeah adjusting the dose um yeah I think you know if uh if if their EF stays okay and their blood pressure is tolerating you know for my end of a few patients of data balance that I was looking through you know they're already on sort of minimal doses of some of these guideline directed therapies so you know maybe they would have to come off those medications because you're already adding a new negative ionotrope with Navigant but I guess in your experience uh Dr Williams or violin have you address it removed their beta blockers calcium chicken blockers there's a pretty strict algorithm okay based on what happens to the gradient in the EF um in terms of you know in in their symptoms um that we have to go through every month and so we adjust their dose essentially on a monthly basis based on what's Happening to their gradient what's happening to their EF and what's happening to their to their symptoms um osm do you want to answer the question about do you have anything else to say about any of those or the diastology component of it and how this might help for diastolic dysfunction so we don't really have data in patients who don't have hypertrophic cardiometrical when we look at the patients with hypertrophic cardiomyopathy this this drug seems to be a losiotrope um it's basically um improves the the myocardial remodeling over time and it decreases the remodeling biomarkers as well but again we have no data in patients who don't have paper trophy cardiomyopathy practice and I just wanted to make one more comment so in terms of you know how to start the medication and and how to adjust other medications as well as you said the we have to enroll these patients into this ramps program which is a safety program um you would typically you know once you enroll the patients and the Rams and adjust the metal content those according to the Rams if the patients are feeling well then I have been either stopping or withdrawing other medications and with that I haven't had any problem so far I did stop uh nor pacing two patients and I was able to down titrate uh beta blockers into other patients as well and with that they did not have any worse meal of their symptoms yeah yeah generally we stopped we stopped dysopiramide if they're on it when we start Navigant um but you can continue beta blocker with the mavic Hampton hi Robbie sir we're out of time so quickly uh so so so like a like all other new drugs we'll be looking for a pleiotrophic uh reason to give this medication and I was thinking about patients with aortic stenosis and hyperdynamic ventricles and those kind of things I guess nothing much has come out on that yet but uh I'm sure it's going to be in the future yeah you're right I mean I think potentially and a lot of hinges on what this does I think the diastolic dysfunction obviously that opens it up to huge groups of patients but right any any sort of condition where you need less or you need negative inotropy this is It's a pretty clean negative ionotrope without a lot of other you know hypotension causing issues you know unlike beta blockers or other negative inotropes so I have a quick question if that's okay sure it's a great talk um but do you know if my Compton is cardio specific and if it is what's the path of physiology behind it um and if it isn't then is there any detrimental side effects on other skeletal muscles and how was it tested by Marco's EMG and Etc yeah it's a it's a cardiac myosin specific um reversible allotary inhibitor so uh yeah it's it's Unique to the myosin the cardiac myosin there so there you know at least I don't know if an animal trials they assessed for any changes in skeletal muscle but you know I think cardiac myosin is fairly unique and contained to the heart so yeah um I I don't know if they did anything in animals but at least in in human it seems to be just specific to cardiac myosin yeah I mean I'm not aware of a nor have I seen any skeletal muscle issues with this drug it does seem to be very cardiac specific and free of really a lot of other side effects to my in my experience so hey Robbie at sixty thousand dollars a year I think I had opted surgery uh is there anything to help patients pay for this uh 90 000 actually stand 90 000. oh I'm sorry I thought it was a cheap truck uh the the drug company does have a program to help folks but you're right cost is is a major cost in monthly Echoes and and a mountain of paperwork are are all barriers um at this point to to getting this drug so right the septal word uh you know so at this point septal reduction therapy is still a very viable um treatment option for for many um and one that many patients choose over over this drug in my in my experience yeah dignified your data from these extension studies will be really helpful though to then sort of compare the differences yeah I mean well look we could go on and on and on uh about this it's a very exciting topic and maybe one we can Circle back to later in the year and and certainly melroy and oslin and myself are happy to to field any other questions offline but for the sake of everyone's time I know everyone's busy and got a lot to do today so we'll we'll uh wrap up here and thanks again melroy for all his hard work and an excellent presentation and we'll see everybody next week the preceding program is copyrighted by Emory University