Can i document type e sign drug testing consent agreement georgia
thank you for joining us for this mda community education webinar my name is michelle barrios and i'm the community education specialist at mda we are thrilled to have you join us today for this important and educational on-demand webinar this webinar today is part of our larger mda engaged flagship community event series which focuses on bringing the neuromuscular disease community together around education and social opportunities be sure to visit the mda engage section on mda.org for updates on upcoming virtual education events before we begin i would like to say thank you to our speakers whom you will meet shortly also thank you to our event supporters genentech and mitsubishi tanabe pharma america we will not be able to provide events like this if not for their generous support so thank you very much the muscular dystrophy association is committed to transforming the lives of people affected by muscular dystrophy als and related neuromuscular diseases we do this through innovations in care and innovations in science md's research is vast we are aggressively working to advance therapy development through support of innovative of innovative research in universities and industry and collection of healthcare data in the mover data hub mda is the largest non-governmental funder of neuromuscular research in the country a single breakthrough can lead to a cure and in 2019 mda supported 252 research projects worldwide our network model means findings from one disease often enable progress in others maximizing the speed at which we can make progress to share a little bit specifically to mda's work in the clinical trial landscape for neuromuscular disease in 2019 mda awarded 25 new grants totaling more than 6.6 million dollars towards research focus on a variety of neuromuscular diseases since its inception mda has invested more than one billion dollars in research to uncover new treatments and cures for neuromuscular diseases with that foundation let us review the objectives for today's webinar participants will learn the process of taking a treatment from clinical trial to fda approval and listen to a firsthand clinical trial experience from a physician next i would like to introduce our first two speakers dr hesterly is executive vice president chief research officer of the muscular dystrophy association she has over 20 years of experience in neuromuscular research in both the nonprofit and industry space she has served as head of research for parent project muscular dystrophy the myotonic dystrophy foundation the association for frontal temporal degeneration and the muscular dystrophy association mda's venture philanthropy dr hesterly has also served as a project lead for rare disease gene therapy programs at pfizer inc as chief executive officer of lion therapeutics a special purpose entity of aspire inc and as executive vice president and head of the neuromuscular disease division of aspire inc she has been involved in numerous efforts to remove barriers to therapy development for rare disease and foster interactions between patient advocacy groups and industry dr hesterly has served on the governing board of the health research alliance the ninds council and the department of health and human services muscular dystrophy coordinating committee she currently serves on the congressionally directed medical research program's duchenne muscular dystrophy programmatic review planner she received her phd in neuroscience from the university of arizona in 1999. dr jerry mendel is the founder of the clinical translational gene therapy program at the research institute at nationwide children's hospital professor of neurology and pediatrics at the ohio state university hosted karen peters chair of pediatric research he is a clinician scientist directing laboratory projects and carrying these to the bedside at the abigail wexner research institute at nationwide children's hospital he has published more than 375 articles with a focus on neuromuscular disease and authored books on disorders of muscle disease nerve disease and gene therapy for muscle disease dr mandel was the first to perform gene therapy for dmd march 2000 2006. he also initiated gene therapy studies in limb girdle muscular dystrophy type 2d showing sustained gene expression for more than six months an important milestone for the field demonstrating potential for gene delivery with safety and efficacy dr manzel led the clinical trial on exxon skipping the first therapeutic agent to show increase dystrophin expression and dmd and now more than a decade later dystrophin expression levels are still increasing and follow-up long-term exxon skipping outcomes demonstrate slowing and disease progression he was the principal investigator on the published article on sma gene therapy that showed unequivocal efficacy this was a milestone achievement because it saves the lives of infants when the gene is delivered delivered in aav9 and very high dose that intravenous administration in addition an important finding was that pre-administration of prednisone one day prior to delivery with extension for 30 to 60 days significantly controls hepatoxicity use of prednisone prednisolone in this way has now become the standard in gene therapy trials this work in sma received science magazine 2017 breakthrough of the year achievement award and the clinical research forum distinguished clinical research award based on this study newborn student for sma is now established in 31 states throughout the country currently dr mandel is actively engaged in systemic delivery of mycodystrophin in a dmg gene therapy and is the first to demonstrate efficacy in this wasting disorder recently published in gemini neurology thank you michelle um so today i'm going to talk to you a little bit about the role of regulatory agencies in clinical trials if you participate in a clinical trial you will certainly experience some of the terminology and you will ideally have a better idea after this talk what the role of these regulatory agencies is is in the different ways that they are involved in clinical trials so this is a very busy slide just to talk about the fact that um drug development is a highly regulated process it can be a long process it can take as long as sometimes 20 years from the time that someone first has an idea that's in basic research all the way through a new drug approval you can see that from the time you get to sort of proof of concept testing in animals through the new drug approval the food and drug administration is involved and they're involved in a lot of different ways even before you get to a clinical trial they still have standards for how you should gather and report data called good laboratory practice later when you get to clinical trial they have standards around a good clinical practice that you have to maintain and as you get into clinical trials in the clinical testing space there are other regulatory agencies that come into play as well including institutional review boards and data safety monitoring monitoring boards there are also specific things that sponsors of clinical trials have to file including an investigational new drug application to test a drug that's for the first time in a disease indication and a new drug application um to get approval of that drug to be able to market and sell it we'll talk a little bit more about all of these regulations and how they come into play so the what the food and drug administration does more or less is responsible for the safety and efficacy of human drugs biological products medical devices um that are in our supply chain and for the nation so they interpret all the rules and laws that govern drug policy and they um also review data that's submitted by drug developers ultimately to determine if the benefits of a new therapy outweigh the risk so why do we need the food and drug administration so if you take a short look at the history of the fda i'm certainly not going to read through all of these bullets but just to say that in general um the history of regulation of drugs in this country has been fairly reactive so um in 19 in the early 1930s there was a drug called sulfanilamide that was sold as an elixir legally but they changed the formula of this drug and it suddenly started killing people one doctor testified that it had killed six of his patients and one of his best friends and it was at that point the congress really enacted the 1938 drug act which was designed to increase safety requirements for new drug testing and again later in 1962 a drug called thalidomide which was designed to help with nausea during pregnancy caused birth defects all over europe but um not in the u.s as it wasn't approved there but it still prompted the fda to strengthen the requirements further to prevent something like that from ever happening in the u.s there were subsequent laws passed over time as well that strengthened the the role of the drug food and drug administration each time finally in 1992 the prescription drug user fee act act was passed by congress to collect some funds back from the various um various companies and sponsors of new drugs and those fees are designed to help the fda operate and that law actually contains a lot of information about how the fda regulates drugs and it's reauthorized periodically when often brings with it opportunities to change how the fda does its its job so there are regulatory agencies all over the world as you might imagine other countries have their own regulatory agencies this is important particularly in rare disease because usually drugs aren't just approved in this country there have to be improved in multiple countries usually just so that there is a large enough number of people who could receive the drug for the company or the developer to be able to recoup the cost of making the drug so all of these organizations have their own set of rules and laws that they follow they're somewhat harmonized and there are various uh alliances and efforts underway to try to harmonize those further so that they're to increase the efficiency of doing this so you're not starting from scratch in each individual company a country a good example of this is the ema the european medical association which governs multiple countries in europe under the same existing law makes that a very efficient process um so for the most part when you're testing a new drug the risks and benefits are demonstrated through clinical testing so clinical testing uses human subjects so if you have been invited to participate in a clinical trial this is where you come in following this long period of testing in animals and gathering research and you know petri dishes when the drug developer finally feels confident to test a drug in the clinic the fda has to approve that um the goal is to determine what is the benefit of the drug whether it has side effects how severe those are and how to manage them um what dose of the drug you should give and finally how it's long the drug stays in the body and how it's broken down so all of these things have to be termed be determined in people before it's legal to market the drug um so just before we talk a little bit more about clinical trials and regulatory requirements just a little bit of useful vocabulary so you've heard me use the word sponsor so a sponsor of a drug trial is really the entity that's legally responsible for that trial and it's usually an institution or company you will probably hear it most often in reference to a company as the drug sponsor but it could be an individual or an institution the clinical investigator on the other hand is the individual who actually conducts the investigation this will be the person who gives the drug and is almost always medical doctor you sometimes hear might hear the word a site pi or principal investigator of a site so when you have a clinical trial with multiple locations or sites there will be a principal investigator in each of those sites an investigational drug is a drug being studied in a clinical trial so a drug is not a drug it's not a treatment it's not a therapy if it's not approved it's it's still an experiment so it's an investigational drug or investigational product placebo is another thing that i'm sure you've heard um there's sort of the bane of the existence of anyone participating in a trial that a placebo is a substance that's ideally not distinguishable from the drug product and the goal there is to make sure that the drug benefit that you see is real and that it's not something that um can be influenced by someone's positive ideas of the outcome this is particularly important in neuromuscular disease where a lot of the functional outcomes are effort-based they're things like the six-minute time walk or various other types of uh functional measurements where really if you are feeling confident you might do better in a trial like that it's not quite as objective as some other types of measurements so placebo can be a very important way to determine that the drug is providing that benefit not just well wishes um biomarker is another term you might hear in in the context of clinical trials so this is something that you can use to give you an idea uh what an outcome is going to be like um without uh it's sort of a surrogate for that outcome so for a good example of a biomarker cholesterol levels which have long been used as a way to understand risk factors for coronary cardiac health what you really want to know is whether or not you're going to have a heart attack your cholesterol levels may help predict that um so you get you the answer faster than waiting for your actual outcome and then finally a clinical endpoint or outcome is something that you can measure that will represent a direct clinical benefit the fda requires that you have an outcome that's clinically meaningful so something you can measure that the drug does that improves uh your life in a way that's meaningful to the person participating in the study so just a little background there because i will use some of these terms as we go forward um so quickly the phases of clinical testing you've probably heard phase one phase two phase three won't go into them in detail here except from the standpoint of where the fda becomes involved so before you can test a new drug the sponsor of the drug must first submit an investigational new drug application so this is a huge dossier that collects all of the data from the animal testing including toxicology testing uh all of the uh proof of concept testing there's a lot of information about manufacturing of the drug and that uh that application that goes to the fda and they don't actually approve it what they what happens is they have 30 days to decide if they're willing to let this trial go forward so if you don't hear from the fda within 30 days you're good to go on the other hand they can look at the information you submit and place the trial on hold frequently they will have additional questions before they release it they may even ask for additional data so if you go forward the phase 1 study is largely safety testing often it's done in healthy volunteers but given the you know with different types of therapy depending on what it is it might also uh the phase one could take place in people who have the disease um phase two or a phase one two um sometimes these phases you'll see slashes because they blur together but a phase two is typically still primarily focused on safety but it also starts to collect data preliminary data on how well the drug works and what the dosing schedule is like these uh phase two will typically test the drug in the people with the condition that it's meant to treat and you can see also that phase two is typically bigger than a phase one study and finally a phase three or pivotal study is the one that is um typically used to generate the definitive data that will go into a new drug application um so these are almost always larger placebo-controlled studies the fda technically requires two well-controlled studies meaning they usually want the placebo in the study um in rare disease they don't always require two pivotal studies it's less common in rare disease than it is in common disease but that is still technically what the
equirements say um so finally um if you get through the phase three and you submit more data you're on the track to an approval of a drug so how does a drugs monster get to market a new drug so if they run that gauntlet they can get to the point of submitting an nda or a new drug application so this is the application that will allow them to start selling the drug so this is a stack of papers this is a very very lengthy collection of all the data from all of the clinical studies all of the pre-clinical data this goes into understanding the benefit safety how well and consistent the manufacturing is done and ultimately contains information on the drug label which is used to decide the label so the label is what describes how and for whom the drug should be given so if you've ever opened medication you get that huge white fold out piece of paper that's the drug label and so all of this information helps determine what goes into the label um when a company or sponsor files an nda the fda has 60 days to decide if they're going to even accept the filing so i think they do a quick pass through it and determine if they see any major missing data or gaps if they do they can actually uh refuse to accept the filing that's called a refusal to file and they send it back to the applicant usually with questions or requests for additional data if it looks fairly complete they will decide to review it and they've got six to ten months on average after that to review the nda um and at that point they can decide if they want to approve the nda following a drug approval the testing still isn't over there's almost always a period of post-marketing surveillance um where this will continue to monitor especially for safety interactions as the drug is delivered to a much wider uh group of participants than you have in a clinical trial so you know your standard um uh clinical trial is really designed to be very uh homogeneous so people as a like as possible so that you can control for all of these variables when it goes out into the general population you might expect that you could see side effects or other things that you hadn't seen in the clinical trial so that will con period of surveillance can last anywhere from you know several years to in case of gene therapy as much as uh five to ten years after administration um there is you know some people ask about full approval versus conditional approval in the united states full approval is the standard almost always when a drug is approved as full approval under rare circumstances you can get a conditional approval which means that the based on data from something like a biomarker which we talked about earlier the fda can decide that it looks very likely that this drug is promising and could be approved especially when there's a major unmet medical need involved and then when the drug is approved it's uh approved conditionally with the idea that the company will go back and continue to gather the data that it needs to show that um there's a functional outcome that also shows this benefit so an example in the u.s would be alexander's 51 which is an exxon skipping drug that was developed by serapto therapeutics and by dr mindel who you will hear from shortly that drug was actually approved conditionally in the united states because of the major unmet medical need in the promise that it showed so there are many ways that the fda can expedite this process i'm not going to go through these in in great detail but you might hear these terms frequently if a sponsor is awarded one of these designations they will put out a press release so you might hear about fast track breakthrough therapy or priority review all of these things are designed to um help a drug either give you more time with the fda or decrease the turnaround time that it takes for the fda to make decisions after various filings or might give you more times to have meetings with the fda um but they're all for various reasons just designed to expedite approval and it could be because it's in a medical need or because the early data look very promising the last one the armat designation really does much of what the top three do but it's specific for us selling gene therapies um but otherwise it is very similar to those top three designations in the benefits that it provides other regulating bodies that you might come across if you're in a clinical trial one is an institutional review board these are made up typically of faculty members at research institutions although there are private institutional review boards as well but these are there to protect the rights of you and anyone participating in a research trial so they want to really make sure that the risk the study is justified by the potential benefit and all the local laws are followed and they are also um particularly involved in informed consent to make sure that if you participate in a trial that you really understand all of the risk and potential benefits and what you're getting into the institutional review board has to approve the clinical protocol that's the study plan before that can go forward so even if the fda has approved an ind the study still can't start typically until the institutional review boards sometimes then each and every site also approve that protocol um the data safety monitoring board is an independent group of experts including physicians and statisticians and often also patient advocates who will review the safety and effectiveness of the trials ongoing one thing about the dsmb is even if it's a placebo-controlled study they typically have access to uh unblinded data as well um the important thing is dsmb based on what they find in their reporting can stop a trial so who all can stop a trial in progress certainly the fda can they can put a study on hold if they see safety concerns the data safety monitoring board can recommend that a study go on hold as well when they review data an institutional review board can actually prevent this trial from starting so these are all different checks and balances that are built in mostly protect the safety of participants involved in the study there's also another role that sometimes you'll hear about an fda advisory board or an ad board um these committees are committees that the fda holds at their discretion sometimes if there are questions about a drug um where the benefits uh little closer than they would normally you know feel comfortable ruling on so they want some outside advice so these advisory boards are made up of external experts um usually with knowledge in the field and they often include some people from the uh community who may or may not have the disease for which the drug is designed to treat so again another example of an ab war there was one held for the approval of exondus 51 which is the drug that i mentioned i had a conditional approval and so many people testified at that ad board and ultimately this is an advisory board the fda doesn't have to take their advice they can listen to it but finally in the long run the fda makes the final decision about whether a drug is approved but it is one way in which the public can interact with the fda and make their wishes known finally access to drugs that are not approved so there's a lot of interest in this topic you might hear the terms compassionate use or expanded access um these are mechanisms by which you can have access to a drug that's not approved um usually if there's some safety data available for it often it will be as part of an a an extension of a um study that's ongoing that might be a phase one or two study but uh the sponsor of the study can identify a population who's maybe not eligible to be in the main study who could receive the drug through expanded access there's also a less common pathway called an individual ind in which a single investigator can submit a new drug or an um an investigational new drug application to treat maybe i think it's up to three to five patients um if there's a major unmet medical need there's also you can do this on an emergency basis so these are some ways in which the fda is a little bit more flexible sometimes with access to unimproved drugs but you really have to justify it well and the important thing to know is that the drug sponsor ultimately has the right to say yay or nay about whether the drug can be made available for this purpose so it's not the fda who controls this um you may have heard about the right to try laws many of the states in the united states i think over 40 have the individual right to try laws and now there's a federal law that also says you have the right to try drugs that are not approved under certain circumstances um in this this is the same situation as the actual existing fda regulation in that the drug sponsor has to agree to make the drug available for this purpose so ultimately you do have the right to request it under either mechanism but the drug sponsor has to agree so this is just to summarize again and say so this is the process we've just typed through again it's highly regulated you can see the different places where um the sponsors have to submit data um there are a lot of ways that protect your safety as a trial participant and it's quite a gauntlet but it does in long run the whole system is designed to save us from incidents like the elixir that killed 106 people um they really want good evidence that the drug is safe as well as uh effective so with that i will say thank you and there are a couple of additional resources listed here both of which are really good um basic primers about clinical trials and fda fundamentals so thank you very much and i will turn it back over to michelle now thank you sharon i would now like to move to our next speaker dr mendel sharon i enjoyed your talk a great deal and in many ways our our discussions here will overlap you have a more technical description and perhaps i hope i can complement what you said with with a practical application and in that sense i'm going to talk about how to get really from the bench to the bedside and i think one of the things that's under appreciated is how planning starts at conceptualization before any lab projects start if you're going to think about doing i'll use gene therapy as the major example i've been involved in translational research for many years but over the last 20 years i've focused on gene therapy and in that context there are three conditions that should be met when you're thinking about doing a clinical trial and this is how i generally teach people who are coming through our lab for for direction and moving their career forward first of all gene therapy should be directed at a disease where there is no known treatment it's a significant step to do gene therapy and there are certain downsides that we'll talk about but you really need you're talking about risk benefit ratio and in that context it should be something that um has no current treatment secondly you need an animal model that closely mimics the human disease often this is a very high bar to set and we sometimes have to compromise as we do necessarily for duchenne muscular dystrophy as i'll mention and then you want to have a a plan in mind that's feasible is the outcome likely to be favorable in that context i like to put it in the in the in the phrase of cost-benefit ratio that means that there's enough patients to treat you don't want to direct a gene therapy trial at a very small number of patients because it's very expensive and so you want a significant incidence of disease this is not to diminish the importance of rare diseases but you need these trials are very expensive so in order to get partners with industry you want to have a significant number of patients who are affected and i like to put it in the context of a very famous a sport at uh sporting sporting event the masters 2005 at which planning should predict a favorable outcome just as tiger's pitch on the 16th green at the masters tournament so keep these things in mind when you're planning you want something that is fairly secure in what you think will develop i'm going to talk about this uh specifically in relation to duchenne muscular dystrophy it's a disease that i'm highly passionate about and i have committed myself to stay in this um in this field and in the gene therapy world until we really have significant outcomes and make a difference for boys with this disease um it's first of all the most common form of childhood muscular dystrophy so it meets expectations about cost ratio benefit and it fulfills as criteria as i mentioned for cost benefit and it's an example to show how the gene therapy is done physically done and i'll walk you through those steps and and it's important because not only is this relevant for duchenne muscular dystrophy but it's other muscle diseases can be treated in exactly the same way with different genes and perhaps different viruses that we'll talk about but the methods are applicable to other forms of muscular dystrophy and in fact we're using we're we're heavily invested in multiple gene therapy trials the sma trial was summarized briefly before and now we have the duchenne trial and we're also involved in limb girdle muscular dystrophy trials so further consideration in planning is if the gene therapy is proposed as a treatment for disease what are the usual questions we get asked i like to put this up front because this is what patients think about and what we have to think about when we start a gene therapy trial where do we get the gene for testing and treatment very common question um and um how does it get to the muscle if this is a duchenne muscular dystrophy trial or a limb girdle muscular dystrophy trial um or there's another target how does it get to the target and and ultimately is gene therapy safe and sharon emphasized this in obtaining an ind and it's absolutely critical and then another question we get for gene therapy is how many times does it have to be given gene therapy is different than exsandus 51 which can be given weekly it's different from prednisone which is given daily or for some patients weekly um but it gene therapy is unique it's a one-time treatment and so that needs to be emphasized the very common question that we get asked so let's look at the history of gene therapy prior to 1999 when i did my first gene therapy trial it goes way back 20 years and the the main approaches to doing gene therapy work and as i'll explain we put the gene in a virus and the virus then carries the gene to our target tissue the main viruses that were used were retrovirus and adenovirus and the reason these two genes were um uh liked for um delivering or for delivering the gene was that the size could accommodate most genes and that's a huge advantage but the limitations were illustrated by historical experiences with retroviruses there's something called insertional mutagenesis and what that means is that retroviruses like hiv insert into the human genome when they insert into the human genome this is insert into other chromosomes they have a very secure place but they might disrupt another gene and in one of the first clinical trials done with with retrovirus for severe combined immunodeficiency disease several of the patients in fact four of the patients ended up having leukemia and one died and that tended to push away retrovirus as a vehicle for delivery for what we call monogenic illnesses it's still used for treating some cancers but it's not used generally for for genetic diseases that are caused by a known gene the other problem is with adenovirus and this is an important distinction by name adenovirus is is a gene i mean is a virus that's very large and it can carry the whole dmd gene duchenne muscular dystrophy gene which is the largest gene in the human genome but it's ideal for that but nevertheless one of the patients who was treated in 1999 with adenovirus delivering a gene called ornithine transcarbamylase the patient developed an exaggerated and uh and very significant immune response and died on the fourth day after delivery and that's a famous case using his name here is not without respect it's one that you can look up in on any internet and it'll describe the jesse gelsinger case so that tended to push the field away
from retroviruses and adenovirus and ushered in the adenovirus associated i had no associated virus as the gene delivery let me emphasize that adeno associated and adenovirus are not the same in some ways it's unfortunate that they have similar names because people get confused about this and and obvious the obvious reason is is is there but there is a reason for that and that and that is that adeno-associated virus requires a helper virus to express an adenovirus is one of the helper viruses that's used to help expression and so it's it's adeno with uh with an association and that's called aav the problem with that had no associated virus or aav as i have shown on the descriptive picture below is it has a very small packaging capacity so if the human dmd gene is 2 million base pairs or more and when it's when it its messenger rna cdna is 14 000 base pairs it can't fit in in a virus if that will accommodate only 5 000 base pairs so that gives us a a problem right from the outset so if we if we look at um but adeno-associated virus has now become the gene of choice for for basically all human uh monoclonal or all human monogenic diseases and the first step in order to make uh the virus work for gene delivery is that you the adenovirus is also adeno-associated virus and let me re-emphasize that if i mess this discussion up because i use these terms overlapping please forgive me aav is what we'll call this aav has only two of its own genes and those are called rep and cap and the reason they're called rep and cap is when when the when the aav is delivered with its own genes rep and cap make a new capsule for the virus or new capsule envelope for the virus and it allows the virus to replicate human gene therapy is not an usual infection it removes the human it removes the viral genes and puts in the gene that we want so it's removing rep and cap so the virus is essentially naked it only has the shell of the virus and what we have to do is load the shell of the virus with a with the gene that we want to use and that's called the transgene or the cassette it goes under a number of different names but have a picture of what this looks like if you look over at the long the picture that goes from above that from the end to the ct that's what the normal gene looks like and the gene that we put in is small and has only um see if this will show up yeah has only this part here the abd that's the amino terminal analogy analogous to the end terminal you see here it has hinges one two one two i'm sorry one two and four that's shown here one two and four and one two and four here but notice that almost the entire middle of the gene is gone now and it has only these repeating units one two and three and twenty four so it has four repeating units and uh and and three hinges and that makes up the gene now how do we know it works in in the development of this process it's been tested multiple times in our own labs we've tested it probably at least a thousand times and we know that it works to to significantly reverse the disease but but animals or mice as we usually use it as the target as the target system are not men as we say in a in a very distinct way men mice are not men and so we can only do a certain amount of prediction from pre-clinical trials now once you have the gene identified like this and you have the virus that you're going to deliver the gene with and i should mention one other thing i'm not sure i have it in another place but the the virus that's devoid of its own genes and the gene that we are going to put in called the transgene those two things together make what we call a vector so the vector is the capsid of the virus the outer shell of the virus plus the gene of interest and none of the genes of that the virus would normally carry and we take that to our vector manufacturing facility now i have a picture of this here because this is a critical step in the development of gene therapy and and i've been at children's now for 16 years i ohio state and children's hospital are linked but i came here i came to children's full-time 16 years ago and when i came i had already done my first gene therapy trial when i was what we say on campus and um and then was asked to develop the program full-time at children's and that appealed to me because my targets were as we now know sma and dmd both childhood diseases but i went to the i went to the ceo of children's hospital i said we aren't going to be in the gene therapy world unless we can make our own virus this is a very expensive detailed process and we put together a vector manufacturing facility and sharon referred to this as a gmp this is this is really what we refer to in the field as a gmp and so we have these various units here in the gmp that can make the viral product and make sure that it has rid of all of its impurities that it it meets all requirements of the fda and anything coming out of this unit has to be a meet fda criteria and then i like i want to show this picture here too to give you some perspective we have all of these serotypes of virus now a serotype means that the capsid of the virus the envelope of the virus has different amino acid structures and we can type those that's where they get these numbers here's aav1 there's a v2 and so forth and now there are a hundred different serotypes and these 100 different stereotypes can target different tissues these are the common tissue common av serotypes in the targets that i'm showing you here but here's skeletal muscle which is what the subject is today and all these serotypes will will be able to express and target in muscle but here here's a the rh 74 and that's what we use this is a bit of a distinctive serotype rh-74 it is um it it is isolated from non-human primates that and uh that's where it gets its name rh and um and the aav 74 is a known is a number nomenclature and the reason we use it here at children's hospital because it was isolated here at children's hospital many of these other serotypes were isolated by other investigators all around the world the most number was by guang ping gaiao when he was working uh with jim wilson and um and and and there's a in the field for better or worse every time you isolate a serotype you patent it when you patent it you essentially own it so if i want to use an aav9 serotype as we did for sma i've got to pay a patent fee to the person who patented this one here we don't have to do that with because we patent it internally at children's hospital so it makes it more easier to use in the long run for us without having to to pay an additional fee for its use we also know from vast experience now that it targets muscle beautifully whether we injected i am or through the circulation we get very high levels of gene expression as you'll see so sharon also mentioned this we before you can do anything you have to show that that your vector as we call it in this case we're calling here's the aav transgene that was the that was the gene that we put in remember when we injected this gene now is going into this virus and has no the virus now has none of its own genes it has only the gene that we put in it and we make this into gmp in millions of copies put it in a syringe and the first thing it takes back to if we go back to the lab and when we go back to the lab and inject it into muscle either directly or through the circulation follow those steps again we inject it into the into the muscle and it courses through the muscle fiber into the nucleus the capsid then is is emptied and the capsid doesn't enter the nucleus it's degraded and only the dna is the first step in that process is often that the dna it depends on how you deliver it but in most cases the dna has to uh the dna is delivered in a single stranded dna and then it has to be made into a double-stranded dna in the nucleus and this double-stranded dna forms an episome a circular form of dna and essentially this is separate now from the chromosomes where hiv and these other retroviruses would insert so it's safe in that sense it has no ability to disrupt other genes and in the double-stranded dna then it then forms the protein of interest and in this case this is called now since it's not the full length dystrophin it's called micro and this is so the gene now in this double-stranded dna forms microdystrophin and now we when we inject it into the mouse what we hope is that this mouse now is has outcome measures that we can measure and are better the mouse is is a reasonable not an ideal model for muscular dystrophy that's why in many cases you have to look carefully at the outcome measures that were used for mouse studies but we also like to see that this same process took place in canine dystrophy and it took and it was also done in primates so that the more assured you are that you have multiple outcomes the the more likely you are to be successful in your trial once this is done we have now we have data that shows that the experimentally well our gene is working and we then have to do what we call a formal toxicology studies formal toxicology studies means that we take 10 times the amount of virus that proved to be effective in our animal studies and show that it's safe in the various species i have a list of pictures here of how many times we use this in order to prove safety and we've done it this shows an example this is in primates now this has been done 142 times in our laboratories here at children's hospital and and looking at all the organs not only the muscle in this case looking at heart diaphragm liver spleen lung gonads kidneys lymph nodes to make sure that there's no pathology that we can see and then we take all this information the experimental data the plan data the experimental data the the clinical trial design and all of these things are put into the ind that sharon mentioned this is an actual picture of an ind i like to show it because it shows how much work goes into it this in this case is an eight inch document and it has to be uh almost hand delivered to the fda in order for um for it to arrive now the be heartbreaking as sharon said for was this to get to the fda and the fda says sorry guys let's try again you need to do more experiments or this or that and it happens but in any case this is what it looks like when it goes to the fda and then then if it's approved by the fda then we take it to our irb and i don't need to reiterate much of this it's the security safety board for our patients and considers ethical considerations ethical considerations are sometimes pretty um i i'd say pretty meaningful or pretty hefty in the sense of um is this something that's likely to work i mean the fd the irb is going to think about that they're going to think about whether this is really a practical solution to the disease and they have the right to reject this they also have the right to reject if you're thinking about an irb for a product that's that's been shown to be effective do you need to do that in a placebo-controlled trial these are all considerations that go into the irb approval and we also have another local institutional biosafety committee that employs nih guidelines to provide oversight for any research using recombinant products just to introduce you to the term recombinant means that the the virus that we use is recombined so now it's recombined with the with the gene and now it becomes a recombinant product so let's look at the next step the next step is to carry it the irb then actually has approved the product the fda has approved this product and now the patients have to approve the product and the parents and patient have to consent for the clinical trial the irb approves the consenting process and the consent form as we use it to make sure that patients understand gene therapy that and then if they understand gene therapy and sign the consent then they have to pass eligibility requirements that are part of the protocol they have to be sure they have no antibody to aav and normal blood tests and a normal physical exam so let's briefly look at these other two important steps antibody has gotten to be a major in some ways a major challenge and even a barrier a certain percentage of patients if we use an aav and let's say aav rh 74 or aav9 which have been two successful ones now one in sma and one in in dmd if we look at these serotypes they're different and and patients can have pre-exposure to these av uh to these virus serotypes it's important to realize though that this aav does not cause a human disease it is a it's a silent infection a little bit like we've heard about covid19 can be a silent infection but but aav as opposed to coven doesn't have its own genes so it doesn't cause any it does and for for gene delivery it doesn't cause any any disease and even in its wild type it doesn't cause a human disease but the exposure can be detected by pre-existing antibody and we must check for that and if there's pre-existing antibody here's a picture of an igg molecule that's localized and localizes to the aav and then it prevents delivery then of the virus and this must be done for any serotype that you're going to use and if it's if it's an antibody that's a to one serotype it doesn't mean it's an antibiotic all serotypes that's an important concept so it must be done for any clinical gene therapy trial that's to be done and the antibody test requires a blood test and it takes about four to seven days to get the lab results back and i also mentioned about uh that there has to be a check for screening for any disease process this shows the major ones we look at are is there any kidney disease is there diabetes is there any liver disease and um and and all and those are probably the predominant ones and we can use uh muscle is challenging because ast and alt are two are two enzymes that are shared with muscle but they we have some opportunity to look at at uh muscle uh look at liver independently i said that wrong liv liver is liver enzymes are shared with muscle and we have to be sure there are no liver complications so we have the opportunity to look at liver alone with ggt and gldh and if you if you're involved in clinical trial in any way with muscle you'll see that these are very important outcomes so you want your patient not to have any ggt elevation or not to have any gldh elevation they will have g they will have alt and ast elevation as part of their muscle disease i hope that's clear then we do a muscle biopsy pre-treatment this is an example of how the muscle biopsy is done in our center we always put the patients to sleep we mark clearly which muscle the common ones we use are the calf muscle and we use the anterior muscle on the lower part of the leg the tibialis anterior we use the quadriceps muscle and we use the biceps muscle depending on the trial and this shows that we do this when we do the biopsy we monitor with ultrasound this is the needle biopsy that we use we prefer needle biopsies because it takes less few it takes a lower a decreased size of the sample by having a decreased size of the sample then we are able to spare muscle and we get enough of a sample that we can then we can then test for the amount of gene that we delivered with microdystrophin expression either but direct staining for counting the number of fibers present or western blot to quantify the amount of of dystrophin that's present this is a very valuable approach to use of the core needle biopsy and then this was actually the first gene therapy trial in dmd that i did back in 2006 i had done actually a limb girdle trial actually before this so this wasn't the first trial i'd done but it shows by example this was a direct intramuscular evaluation monitored by ultrasound with a interventional radiologist standing by to help isolate the muscle we're no longer doing these direct intramuscular injections for the most part we do vascular delivery we it's not unusual for a gene therapy program to start with a safety trial first in muscle then a limited vascular trial than a systemic vascular trial and this is an example now of a systemic vascular trial which we do routinely now this shows the virus as it's delivered from the um pharmacy this is the actual volume for this patient that's calculated based on weight we load this i
to a into a an infusion pump like you see here and and then the infusion pump then we is set for how many how much we want to deliver in general we deliver the virus over an hour to an hour and a half the patient is awake during the delivery there's almost no feeling from the delivery as we put it as we put the virus in and that and then here's exactly how look this is a real picture of a real patient getting a virus it's delivered in one arm we keep an iv open in the other arm in case there's any blockage or anything that should occur here on delivery and we can switch this over very rapidly we monitor heart rate and basically an ekg and respiratory rate and temperature all during the trial and and then after the test is over we monitor blood tests the same ones i mentioned we monitor kidney function glucose function monitor liver enzymes those are the ones we concentrate on most the alt and alt are elevated as part of muscle but at baseline their ggt and their gldh are normal ggt here gldh here elevated ast and alt from their muscle normal liver function post delivery though we commonly see liver elevate liver enzyme elevation i won't discuss all about that that can be part of a question period but liver enzymes are common form of aav what we consider an av adverse event we suppress these elevated liver enzymes with prednisone even though the patients and duchenne are on prednisone will give additional prednisone uh to block the liver enzyme elevations the manifestation of inflammation they feel nothing from it incidentally there's usually there's virtually no systemic manifestation of this in terms of of patient toxicity or patient symptoms now um i i like to show this picture because this is an actual picture again of a patient who we just finished delivery on i like taking the picture here shows the patient has virtually no feeling had no problems during delivery as happy as a lark so to speak and not any problem but shortly after gene delivery the common side effects are we do see nausea and vomiting usually starts around the second or third day may persist up to three or four weeks sorry and we often have loss of appetite elevated liver enzymes we may have transient platelet decrease all this is um the the the liver enzymes and the platelet decrease are not symptomatic but of course nausea and vomiting are and then during that during the patient stays in the hospital usually one day after gene delivery and then both pre and post gene delivery we will will do outcome measures the most common one we do that we rely on is called the north star ambulatory assessment these are three of the tests that are part of the north star ambulatory this patient here is uh his scored and how well he stands up this one in terms of lifting head and trunk control and this one's stepping up on a step board as you can see here in addition to these we do and sharon mentioned this other outcome measures are are the uh are the 100 meter walk run test climbing stairs these are time tests very quantitative and allow us to between the north star and these other measurements we can comparing pre and post gene delivery measure efficacy and this is the just quickly show you oh this has been published now so it's not embargoed any further this is our one year clinical trial in our in the recent systemic gene delivery all measures have improved the north star time to rise four standard stairs in the hundred meter and we're now into a double-blind randomized controlled trial that has extended this now to additional 40 patients and i'd show this this is from our current trial and i like to show up here this is 18 months post gene therapy and we can see how well he gets up from the floor and finally this is the gene expression data from our first trial we have very very high levels of gene expression in the muscle that reached 80 percent across the board as you can see here and this one actually reached over 90 so very favorable uh outcome measure here and so this is um how the clinical trials work in progress the collaboration is between patients families and and all of the staff in the gene therapy center these are the prominent players in our gene therapy center who are involved in the clinical trials and also this trial has been done with serapta as the as the industrial sponsor and two people to highlight there have been very helpful louise radino clay pack who's a scientific director at srapta and she was one of my former fellows and now has far uh far exceeded me in terms of an industry place position and teji singh who's one of the leaders in the clinical trials at serapto so these are the experience and i'll end there and turn it back over to michelle thank you sharon and dr mandel we sincerely appreciate your time and expertise and everything you do for the neuromuscular community the information you shared today was incredibly valuable and education also thank you again to our event sponsors genentech and mitsubishi tanabe pharma america we would not be able to provide events like this if not for your generous support so thank you very much if you have any questions around the mdh program and or items from this webinar please feel free to email them to mdaengage mdausa.org and we will do our best to answer them do also remember mda's resource center is a wonderful resource for mga's families the mda resource center is available to provide one-on-one support via phone or email for individuals and families looking for information about the diseases and mda's programs and more this concludes the mda engage webinar clinical trials from design to fda consideration thank you very much for watching today and we look forward to you joining us for future webinars and additional educational events
