[Music] from the JAMA Network this is JAMA clinical reviews interviews and ideas about Innovations in Medicine Science and clinical practice hello I'm Chris Muth Deputy editor at JAMA and I'm here today with Dr Gil Rabinovici to discuss an article published in JAMA called dananamab in early symptomatic Alzheimer's disease the Trailblazer alls II randomized clinical trial Dr Rabinovici is a neurologist and dementia expert and he is a professor of Neurology and radiology at the University of California San Francisco he was also a co-author of an editorial published in JAMA that accompanied the Trailblazer alls2 trial thank you for joining us today Dr Rabinovici you co-authored an editorial that accompanied an article published in JAMA about a randomized clinical trial of dinanimab in early symptomatic Alzheimer disease but before we get into the specifics of that trial I'd like to begin by taking a step back and discussing this class of medications more generally the nanomab is one of several different monoclonal antibodies that all target beta amyloid and I'm wondering if you can explain the rationale for this class of drugs and why they're being studied in Alzheimer's disease well thank you for having me it's really a pleasure to be here so for many years the prevailing hypothesis about the pathogenesis of Alzheimer disease has been grounded in the amyloid Cascade hypothesis so just to remind everyone Alzheimer's is defined neuropathologically by the accumulation of amyloid plaques that are composed of aggregated forms of amyloid beta and neurofibrillary Tangles that are composed of aggregated forms of hyperphosphorylated Tau protein and it's really the combination of plaques and Tangles that Define the disease now early genetic observations in the 1990s found that about the one percent of patients who develop a familial form of Alzheimer's disease with autosomal dominant inheritance have mutations that cause the overproduction of the amyloid beta polypeptide and this really led to a large body of work that has demonstrated that the aggregation of amyloid beta triggers a Cascade of events that ultimately result in dementia amyloid beta Aggregates are directly neurotoxic they affect synaptic function and network function they generate what ultimately turns out to be a maladaptive neuroinflammatory response and they prompt the hyperphosphorylation of Tau protein which leads to aggregation and spread of Tangles and it's then the spread of the tangles that leads to synaptic loss neurodegeneration and ultimately memory loss and dementia so the monoclonal antibodies Target different forms of a beta Aggregates and the idea is that if you can remove a beta from the brain using an antibody approach you can slow down this Cascade of events you can mitigate some of the Direct neurotoxic effects of amyloid beta and more importantly you can also try to slow down or prevent some of the downstream Cascade of events that occur that lead to dementia and by removing amyloid beta from the brain the hypothesis is then that you can slow cognitive decline okay great and so there have been a lot of different antibodies that have targeted amyloid throughout the years and I think we've seen a lot of trials that have been unsuccessful and then more recently over the past few years things in the news have been popping up about positive studies or potentially positive studies could you kind of give just a brief overview of how things have evolved and where things stand now with some of the more prominent medications that we're hearing about lately of course so there was really a steep learning curve involved in developing this class of drugs one of the major things that facilitated more success in the past few years is the development of biomarkers that can actually directly measure plaques and tangles in the living brain early on the trials were unsuccessful possibly because we were enrolling the wrong patients patients who were diagnosed with early stage Alzheimer's based on clinical symptoms alone but may not have had plaques in their brain it turns out that the clinical diagnosis in isolation without including a biomarker to show give us biological evidence of Alzheimer's disease the accuracy is only about 30 to 50 percent compared to autopsy one of the major biomarkers that have been very helpful in developing this class of drugs are positron emission tomography radio tracers that bind either to amyloid plaques or to town neurofibrillary Tangles and these allow us to select the right patients into the trials and also to determine if the antibodies are working if they're actually removing plaque from the brain by showing a reduction in pet signal and so really the integration of biomarkers into drug development was what led to I think more successful trials in more recent years so the first drug that made it to the clinic was a drug called agricanumab this was a monoclonal antibody that very robustly removes plaques from the brain Jama and many other journals have published the controversy that occurred when the FDA granted accelerated approval to this drug in June of 2021 based on this robust biomarker signal because the phase 3 clinical trials looking for clinical efficacy C were actually terminated early based on a pooled futility analysis later on it turned out that one of these phase three trials hit its primary a clinical endpoint the other did not and so the FDA granted accelerated approval to Edge Academy map based on a biomarker signal but the clinical efficacy I think was very uncertain and that generated a lot of controversy in the field about a year later another monoclonal antibody called locanamab completed its phase 3 trial called The Clarity ad trial and this gave a much clearer answer so Locanto map like agricanumab robustly removes amyloid plots from the brain but in this case the phase 3 trial was completed not terminated early and in fact showed that the drugs slowed the clinical decline of patients compared to Placebo by about 27 percent the trial also hit all its secondary endpoints which also looked at cognitive and functional outcomes and so this was a pretty clearly positive clinical trial and on July 6 of this year 2023 the FDA granted traditional full approval to locator map for the treatment of early stage Alzheimer's disease based on demonstration of clinical efficacy in a phase 3 trial and so prior to a drug that we will talk about today there are two antibodies that are approved for clinical use one is actually cannamab which is just granted accelerated approval and the other is lecanumab which was granted full approval in July of this year okay great that's a great segue into our discussion of this trial of dynanimab the Trailblazer all's II trial which is a phase three trial recently published in Jama can you talk to us a little bit about dynamab and this trial including the types of patients that were enrolled touching on some of those biomarker criteria that you had mentioned earlier sure so to name a map is yet another antibody as opposed to the two antibodies that we've just discussed at chicanumab and locator map which bind to earlier forms of a beta Aggregates before the mature plaques this antibody actually binds to an epitope that is only present on mature plaque so of all the antibodies that have been tested this one is most specific for the plaques and this trial built on a successful phase two basically in this trial about 1700 patients who had mild cognitive impairments MCI or mild dementia due to Alzheimer's disease and demonstrated evidence of plaques and Tangles on pet scans were randomized to receive either to nanomab infusions or Placebo every four weeks the primary endpoint in the trial was a clinical scale called the integrated Alzheimer's disease rating scale or iadrs which is 144 point scale that combines measures of both cognition and function so things that are very highly relevant to patients and in the study a study lasted 76 weeks patients in the trial were stratified based on the amount of Tau accumulation that was found on pet scans they were stratified in either into a low to medium Tau group people that had evidence of Tau pet uptake but the uptake was not very high or an overall study population which included patients that had both low to medium and higher amounts of Tau in the brain so this is a difference this is the first clinical trial to actually stratify patients based on the amount of Tau accumulation which may turn out to be very important and patients were treated for 76 weeks and at 76 weeks there was about a 35 slowing of clinical decline as measured by the iadrs scale in patients in the low to medium Tau group compared to Placebo the effect in the overall population was smaller about a 22 percent slowing still significant compared to Placebo on the primary endpoints and the trial also looked at several secondary endpoints including plaque removal again this was very robust in fact maybe the most robust plaque removal that we've seen based on pet scans in these antibodies so far with over three quarters of patients showing complete removal of plaque based on pet scans and then additional cognitive and functional skills all of which showed somewhere between a 20 to 35 percent slowing of clinical decline compared to Placebo and so this trial met its primary and second Dairy endpoints and is therefore a positive trial now the second clearly positive phase three trial in this class of anti-amyloid beta monoclonal antibodies great and I think as you mentioned nearly all of the primary and secondary outcomes showed statistically significant benefit of dynamab a question that comes up a lot is the differences may be statistically significant but are they clinically meaningful can you talk a little bit about how clinicians and patients might think about the clinical meaningfulness of the findings and what you think the case is based on this study yeah this is really challenging because this isn't a treatment where patients improve in terms of their symptoms or their function they don't stop declining on average but they just show a slow a slowing of that reduction so how do you determine if that's clinically meaningful there were a couple of exploratory analyzes in this study that tried to get at that one was looking at conversions indices States so we talked about the fact that the study enrolled patients who had mild cognitive impairment or MCI this was about 60 or so of the patients in the trial MCI means that people have significant memory loss but they're still fully independent in their daily activities and the other group of patients that were enrolled have mild dementia meaning they require some assistance in some of the higher order daily activities like managing finances but they're still able to do a lot of things for themselves and the authors asked how often did patients convert from having MCI from being fully independent to mild Dementia or for those who entered in the mild dementia stage how often did they convert to having moderate dementia meaning that they required more help with some basic self-care over the course of the trial and what they found was that there was about a 40 percent lower risk of progression in disease stage for patients who were treated over 76 weeks compared to Placebo so this is I think a metric that can be very meaningful to patients are you independent or do you need some help do you need help with the more difficult tasks of daily living or do you need help with some of the more basic tasks of daily living these are really concrete disease stage transitions that I as a clinician can talk to my patients about in discussing the potential benefits versus risks of the treatment the other way they approach this was looking at time saved in terms of decline in these clinical skills two clinical skills that they looked at were the iadrs the primary outcome and another very common outcome in Alzheimer's disease clinical trials called the clinical dementia rating sum of boxes and what they found is that treatments slow decline on these scales anywhere between four and a half to seven and a half months during an 18 months course of treatment so again this idea of time saved time that patients are maintained in a better functional States these are things that I think are meaningful to clinicians and to patients and can be discussed we'll we'll talk about some of the risks of the treatment as well as you know the requirements of patients we're undergoing treatments and I think some patients will decide that these benefits might be worthwhile in terms of the potential risks to them and the burden of treatment others may decide that it's not worthwhile but I think these exploratory analyzes to me were very helpful in grounding the clinical meaningfulness of the treatment in metrics that I can wrap my head around and discuss with patients as opposed to something you know more abstract like slowing of decline on on the clinical scale that's very helpful and you mentioned adverse effects and so I think it would be great to dive into that now so for this class of medications as a whole can you comment about some of the potential adverse effects in terms of the overall class of drugs the monoclonal antibodies and this particular drug to name a map I think the side effect that is most concerning is something called amyloid related Imaging abnormalities or the acronym is Arya which manifests as MRI changes either edema or effusions or hemorrhages typically micro bleeds but occasionally macro hemorrhages and these occurred in higher proportion of patients treated with the drug than in Placebo the Aria that presents with edema effusions is called Arya e and that was present in 24 of patients treated compared to two percent of placebo and the Aria that presents with Hemorrhage is called Aria H that presented in 31 percent of patients treated compared to about 14 of placebo and so these are I think the most concerning risks associated with the treatment one really important aspect and this seems to be true across this class of drugs is that the risk of Aria in particular Arya e is highly related to an individual's apolipoprotein e genotype APO E4 is a risk Gene that is associated with sporadic Alzheimer's disease and it was also very strongly associated with Aria so everyone has one of three types of apoe either apoe3 that's the most common genotype apoe2 which is actually protective against Alzheimer's disease or apoe4 which is the risk Gene and in this trial Arya e occurred in about 15 percent of people who did not carry a single apoe4 allele it occurred in 23 percent of people who were heterozygous for apoe4 and it occurred in over 40 percent of individuals who were homozygous for apoe4 and so there is a clear dose-dependent increase in the risk of Aria associated with apoe genotyping this is really important in fact in their prescribing information for locanamab the previous antibody that received full FDA approval the FDA issued a black box warning about Aria in particular related to APO E4 homozygous again they're at higher risk of developing Aria they're also at higher risk of developing recurrent or severe Aria and so in clinical practice we had not been testing apoe genotype routinely in diagnosing or treating patients with Alzheimer's disease but because of this pharmacogenomic effect on the risk of Aria the recommendation in the FDA prescribing information for lecanumab and my guesses this may also occur for dnanumab is that these genotyping be done prior to treatment so that patients can be fully informed about their risk of developing Aria Arya sounds very scary and in fact it can be but I want to emphasize that in about three quarters of cases there were actually no symptoms associated with Aria and so the Aria was detected when based on surveillance MRIs that were done for safety purposes with patients having no symptoms and with pausing or slowing treatment Arya often resolves radiographically that said in the 25 percent of patients who have symptoms of Aria those symptoms tend to be mild and fairly non-specific a little headache dizziness a little more confusion however in rare cases Arya can lead to severe symptoms such as stroke-like episodes seizures malignant hypertension occasionally Aria requires hospitalization or even ICU care and in extreme cases Arya can lead to death in this trial three patients died in the setting of severe Aria events and and so this is a rare but very serious complication associated with treatment and something that will need to be considered by patients and clinicians who are prescribing these drugs that's a great summary and I think it's you're starting to touch on some of the Practical aspects of potentially using these drugs in the clinics in terms of talking with patients about risks and benefits and then some of the things that have to go into the use of the drugs including monitoring patients for safety events and for treatment response could you talk a little bit about the practical considerations as these drugs seem to be moving from clinical trials potentially into the clinics there is a really large gap between our current clinical practice in terms of diagnosing and caring for patients with Alzheimer's disease and the implementation of this new class of therapies which requires really very intense surveillance as you say and the use of biomarkers so in this trial patients were selected based on an early clinical stage of MCI or mild dementia and biomarker evidence of Alzheimer's pathology in the case of the trial amyloid and Tau pet scans were used to confirm the presence of plaques and tangles pet scans are not widely accessible in clinical practice they are not currently covered by most insurance and so there immediately is one challenge of translating the design of the Trailblazer ALS to study into clinical practice fortunately there are other biomarkers that tell us with high reliability whether patients have plaques and tangles in their brain the most accessible and one that is generally covered by insurance is a cerebral spinal fluid assay that measures the concentrations of the amyloid beta total Tau and phosphorylated Tau proteins in the CSF and those assays are actually FDA approved now and very reliable in detecting pathology so I suspect that in clinical practice people might use CSF biomarkers one really exciting development is the advances in blood tests that can again with very high accuracy tell us about the presence of plaques and tangles in the brain some of the seminal articles validating these blood biomarkers have been published actually in Jama and my hope is that I think these assays are very close to Prime Time and the hope is that they might actually be the biomarker of choice in terms of confirming who has Alzheimer's pathology I think because the risks of Aria are very real we will need to be quite conservative in who is treated and there are appropriate use recommendations for the other two approved antibodies likely there will be appropriate use recommendations developed by experts for this antibody to natomab as well that basically align very closely with the clinical trial inclusion and exclusion criteria the idea is that the safety of these drugs have really been studied in quite a narrow population of patients and at least as we start to roll this class of therapies out into practice we will probably want to follow quite closely the clinical trial inclusion exclusion criteria in order to make sure that we're treating the right patients and patients in whom we have some assessment of safety and then this will require also replicating the MRI surveillance which requires quite frequent MRIs especially early on in titration of the antibodies when Aria events are most common in order to make sure that we detect Arya early on remember usually it is asymptomatic and it resolves if you catch an early pause treatment and allow it to resolve but in order to do that you actually need to go ahead and conduct the MRI surveillance very close to how it was done in the clinical trial this treatment requires monthly infusions and so this is quite an intense treatment with a biomarker study monthly infusions and frequent MRIs in order to assess for safety detect Aria and make management decisions based on Aria so this is really a huge gap from where we currently are in terms of treating Alzheimer's disease and I think you know even in academic centers such as ours at UCSF where we have been conducting clinical trials of these anime bodies for many years it's quite a heavy lift to implement this into our practice and I can imagine that may be even more so the case in other types of practice settings that did not have experience with these treatments so I think there's going to be some catching up to do there will be a gap of time in being able to provide these treatments reliably and safely in general clinical practice but ultimately this is really going to elevate care and Alzheimer's disease it is going to entirely change how we practice our diagnosis I think we're going to be using biomarkers quite often now in order to establish the diagnosis and it will really transform the type of care that we're able to provide our patients instead of just thinking about cholinesterase Inhibitors or mementine symptomatic drugs that slightly enhance cognition we're really thinking now about modifying the course of the disease and so there will be many challenges ahead as we think about implementation but this is also a tremendous opportunity to elevate care across the field and provide better care to patients who are currently have Alzheimer's disease and their families I think that's a great summary I'm another thing to consider is when a patient is treated with one of these monoclonal antibodies how long will they need to continue to receive the treatment so this is a really Innovative aspect of the Trailblazer ALS to study previous trials have just treated patients with antibody for the duration of the trial in this trial they actually titrated the duration of treatment to the pet scans amyloid pet scans were conducted at 24 weeks and again at 52 weeks and if patients had actually demonstrated that amyloid plaque had been cleared on the Pet Scan they were transitioned from active treatment to Placebo so now instead of thinking about treating people indefinitely with antibodies you're really treating people until their plaques are cleared and the study successfully hit its clinical endpoints using that strategy and so when we think about the cost and patient and clinical burden of these treatments it becomes much more feasible to imagine this as a limited duration treatment that lasts six months a year maybe a year and a half until plaques are cleared and then treatment is actually halted and patients are now observed this becomes something that's much more attainable for our health care System than indefinite treatment with antibodies so that is a very exciting innovation in this trial and may inform how we use the other antibodies as well great so for sure there's going to be as you mentioned challenges with access and Equity but at least one potential bright spot is that this may not need to be a treatment that goes on indefinitely are there any other final thoughts you want to offer in terms of either this study on the nanomab or the treatment of Alzheimer's disease with monoclonal antibodies against amyloid beta more broadly or even how you might think about talking to your patients or positioning this as a treatment for the care of dementia you know I really want to emphasize what an exciting time this is in the field because you can see the convergence of the biomarkers and the therapies coming together to really revolutionize how we provide care I think that this is a really significant advance that brings a lot of Hope but I think the limitations of the monoclonal antibodies are also becoming clear with multiple drugs now showing very consistently that the magnitude of the effect is about 25 to 35 percent slowing of clinical decline as we discussed that may be clinically meaningful but obviously we want to aim higher in terms of the magnitude of effects furthermore we know that these drugs come with significant risks we discussed Aria and so I think that this is an important advance and I think these drugs will provide benefit to some carefully selected patients but I really view this as just the first class in a new era of molecular therapies for Alzheimer's disease I think it is very likely that we will need to Target other targets Beyond amyloid beta to have a more profound effect on the course of the disease I think we might really think about treating patients or individuals in the pre-clinical stage when they have plaque buildup but don't yet have symptoms amyloid lowering at that stage might have an even more profound effect and so I really view this as just potentially the opening chapter in a new era of how we provide care for patients with Alzheimer's disease and other related neurodegenerative diseases great thanks so much for taking the time to speak with us today Dr rabinovich that's all for this episode there's a link to the report of the clinical trial that was published in Jama in the show description in addition to Dr rabinovich's editorial which was co-authored by Dr reyno LaJoie there are also three other editorials published in Jama that address various considerations related to access cost equity and the clinical implications of monoclonal antibodies targeting beta amyloid for the treatment of Alzheimer's disease for more of our podcasts you can find us at jamanetworkaudio.com thanks for listening