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New Advances through the lens of Hemophilia

May 02 | 2:00 PM

Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Let's understand some top revolutionary advancements through the lens of hemophilia with Dr. Savita Rangarajan.

[Music] so good evening everyone this is dr rishali and i welcome you on behalf of team netflix for this session on new advances through the lens of hemophilia today we have with us internationally known clinician in the field of hemophilia dr savita rangarajan with more than 25 years of experience and i am extremely honored and grateful to have this opportunity to introduce her after completing her specialization in hemophilia at the royal college of pathologist she worked at guys and saint thomas nhs foundation trust for 14 years then she joined hampshire hospital's nhs foundation trust in 2008 to build and lead on the hemophilia hemostasis and thrombosis service which led to the development of the southern hemophilia network in 2012. during this tenure she has been an integral part in developing a nhs innovation award-winning telemedicine application she is also involved in setting up a comprehensive care center in mumbai in 2015. she is also the founder a member of the scientific and academic coagulation consortium which enables collaborative research between academics and clinicians who are experts in their field in the uk as network directors she has overseen the growth of the southern hemophilia network to encompass a network of hospitals across the whole of the south of england her strength and passion lies in increasing the access to expertise and treatment for all patients with bleeding disorders globally so massive massive experience ma'am and great accomplishments uh really it was my pleasure to introduce you today with this ma'am i'll hand it over to you thank you thank you for the very kind um introduction and thanks to netflix for inviting me to talk about the hemophilia story i'm going to talk about the recent developments in hemophilia however my title of the today's talk is called genes to gene therapy so i think most of you know what hemophilia is hemophilia as a disease is called a severe disease if factor eight or factor nine is less than one percent i'm going to talk mainly about hemophilia a today which has factor eight deficiency now what happens in patients with severe disease is that they get repeated and traumatic bleeding into joints and to certain tissues and of course if it does occur in the brain it could be fatal inevitably this leads to chronic arthropathy and morbidity and has a massive impact on the quality of life we all know about the royal connections it is called the royal disease not necessarily because of the royal connection but also because of the fact that the cost of treatment in hemophilia is quite something and clearly only the royals can afford if they were to pay it off to the pockets i just quickly want to talk about uh the hemophilia history in 2280 the babylonian talmud records fatal bleeding during circumcision in the first son of each of three sisters again then only in the 12th century maimonides who was a distinguished physician as well he recognized that a woman transmitted the disease to her sons and therefore he came out with a degree that in jews once there was one sister whose son had had a circumcision and day and died after due to fatal bleeding the second sister did not need to circumcise any of her further sons it was in 1803 that john otto presented an account of an hemorrhagic disposition in some males of a family in plymouth new hampshire most famous link obviously i've already mentioned is the royal family queen victoria being the obligate carrier and this was factor nine it was hemophilia b however this gene was transferred to the russian and the spanish royal thrones the tsar of russia was so preoccupied with his son alexis ill health that he was unable to take firm decisions leading to the first world war we believe and that rasputin the guy who all of you know as rara respite in the song that made him so famous rise to fame for his ability to treat the bleeding condition so where does hemophilia care globally 70 of patients across the globe don't have any treatment not not much treatment rather many children die early on because of as i already mentioned the high cost and it is a low priority for many governments more importantly even the investigations that are associated with the coagulation disorders are not available everywhere it is a rare disease but patient numbers are low worldwide technically speaking because it is rare disease however that is not necessarily the case in india purely because of the sheer population we believe there should be anywhere between 70 000 to 100 000 patients however the last count is somewhere between 20 to 25 000 in india registered patients this is what happens in patients who have a bleed into the joint as you can see on the left side that is an acute joint bleed with synovitis and then following on after multiple bleeds they go into chronic arthropathy where there is a burnt out joint so our goal in the management of hemophilia is to stop the crippling effects of hemophilic arthropod so what happens is repeated bleeds into the joints causes the destruction of the joint tissues by the proteolytic enzymes that are released this leads to destruction of the cartilage destruction of the subchondral bone thereby and bone resorption and ossification this forms the joint deformation and impaired joint function that was noted [Music] so i wanted to talk a little bit about the development of hemophilia therapies that was mainly driven by the safety needs and i point out safety needs as a very key example because obviously in the 1975 to 1980s we were issuing mainly dry precipitate plasma but also there was concentrates factor rate constant plasma derived factor rate concentrates however around 1980s and there is when hiv struck and many patients with hemophilia did develop hiv because of the plasma that was being used so then came the treatment and then improved measures to to contain transfusion transmitted infections so that came about till 1990 and in 1992 is when recombinant factor 8 was being made available there were clinical trials and it was made available to make the safety issue much better at least from the infection perspective then of course what we didn't know was hepatitis c that too struck a lot of patients with hemophilia here is professor turner who origina who is a very dear friend of mine and he actually cloned the factor eight gene in 1982 and it published in 84 the the the characterization of the factorate molecule and its gene genetic code which then led to the recombinant factory the reason i put his photograph here is because he then led the gene therapy program as well so this is why my talk is called genes to gene therapy because he was the one who actually had cloned the gene first and then obviously went on to gene therapy so the seminal paper in 2007 in the new england journal was published where it clearly showed that patients with hemophilia which was a randomized study and it clearly showed that patients who had prophylaxis did a lot better than on episodic or on demand treatment the number of bleeds were reduced to significantly nil if they were on prophylaxis but more importantly it was a joint disease that was significantly improved while stomach prophylaxis and the joint score was much better while strong prophylaxis so that led us to believe that we did require significant factor eight to be available in the body to prevent damage so you can imagine that when we give factor say monday wednesday friday or do if we were to give alternate days there is always going to be a trough and a peak so we actually have a soft tooth expression where the as soon as we give factor it goes up and then it falls so it's kind of what we call the sawtooth appearance with the extended half-life or ehl factor the artificial the tough problem the sawtooth problems still remains and we accept that it is a bit further away in the sense because of the longer half-life it can be seen to be not so sharp as in the normal factor i'm going to go through the non-factor therapies shortly and of course gene therapy where we take away this tough problem and we have a steady state level or factor so the replacement therapy with factor eight clearly reduces bleeding as was shown in the mango john's in new england journal paper and to prevent hemophilic arthropathy for patients with severe hemophilia a however there are a lot of barriers to current hemophilia a treatment one is multiple intravenous infusions that are required the hemostatic control for patients with inhibitors which is difficult so what happens in hemophilia a is there are a number of patients or or rather 30 percent of the patients with hemophilia a are prone to develop what we call inhibitors to factor eight so when you give somebody with a when they don't have any protein that is factor eight you can actually develop antibodies against a foreign protein that is factor eight that is being given to them and thirty percent of patients with hemophilia a do develop antibodies to factor eight which means that they cannot be given factor eight anymore to correct their factor and we have to use something called bypassing agent which bypass factor 8 in order to in order to cause to promote a throat formation the cost of bypassing agent is extremely high let me give you an example of two bypassing agents one of them is called fiber which is factor eight inhibitor bypassing activity and the other one is called number seven or recombinant factor 7a so if you have a bleed in a patient with inhibitor you need to treat a 70 kilogram person would require 7 milligrams of nova 7 on two occasions two hours apart which makes it 14 milligrams and the cost of one milligram of nova 7 is around anywhere between 40 and 40 to 50 000 rupees so you're actually looking at a cost about 14 to 15 lakhs per bleed treatment which means if if a person bleeds twice a month which is actually not enough most of the patients would say hemophilia bleed at least four times a month but even if you did bleed twice a month that is going to cost you anywhere between 20 to 30 lakhs a month which again as i said probably only the royal family can afford now to help overcome these barriers there are new medications that are available which one of them is called a bi-specific antibody which acts against factor 9 a and 10 and i will talk about that in a bit more which acts like factor 8 a or 8 a mimetic rnai or rna interference targeting anti antithrombin and anti-tfbi or tissue factor pathway inhibitor antibodies so these are disruptive technologies so we are not giving like for like we're not giving factor eight to the patient who's got a deficiency we are using something very different in the treatment of hemophilia to manage the problem of bleeding this disruptive technologies clearly have benefits but any ben any of the new technologies don't come without any risks the benefits clearly are the potential for improvement with the current standards of therapy risks usually not immediately obvious there are no knowns we don't know of certain problems that are there there are more known unknowns and unknown unknowns to to be frank there's a lot we don't know about it so the most important considerations for any treater is do not do any harm particularly in hemophilia patients who we know with prior encounters with viruses etc and premature miracle therapies we know that there have been problems before so let me go through what factor 8a does first in the clotting system so 8a factor 8a is important to bring together factor 9a and factor 10 it then releases activated 10 which then in consort with factor 5a activated 5 and prothrombin releases thrombin now thrombin generation is the most important actor in the whole coagulation charade and then causes the clot to form thrombin you need the tennis x and to form the tennis complex factor eight a is very important specific antibody has two specificities one of them is to factor 9a and the other one on the other arm it brings the factor 10 together and does the same job as factor 8 which is factor 18 mimetic this is called a hem libra or any suzy map and it and as i said it places the factor 9a and 10 into spatially appropriate positions to my mic to mimic the allosteric cofactor function of factor 8a so the features are that it is subcutaneously it is subcutaneous and because it's a fact it is an antibody it's got a long half-life it is effective in patients whether they have factorate inhibitor or not because it is not factorate itself so we can use it in inhibitor patients and it is also not likely to induce factor eight antibodies because it is not factory so therefore it ticks all the boxes and it is extremely good i think it is a blockbuster drug and it is currently in use everywhere so we did the trial af for this particular drug even in india called the stacy trial and the publications are due for that soon although the drug is licensed now i'm going to talk a bit about rnai which is as i said rna inhibitor inhibitors and these are a new class of innovative medicines there are a lot of um rnais already a couple of them in the market and one of them was recently used for cholesterol reduction as well includes iran um this drug for hemophilia is called fetuseran and it harnesses the natural pathway and it is a catalytic mechanism by which it can silence any gene so for for example the mrna that is formed of any protein is catalyzed and therefore the protein is not produced it silences any gene it is upstream of any medicine today's medicines and it is a clinically proven approach as i mentioned so we publish this again in new england journal targeting of anti-thrombin in hemophilia aob with rnai therapy this was in 2017 this was a phase one study that we published so the whole idea of fiduciary it is still an investigational drug we are doing the phase three studies currently and we have a lot of patients in india as well who are on fiduciary so what does fiduciary actually the whole concept of fetus ran is that it is a subcutaneously administered drug again as i said it targets antithrombin so so it it reduces the the um the uh mrna of antithrombin and therefore antithrombin production is significantly reduced we try to reduced it reduce it to about 15 percent uh okay so it is significantly reduced it isn't it is non-biologic chemically synthesized and it really targets the liver where mrna of where where antithrombin is produced so the whole idea is it is a rebalancing of clotting meaning when you have hemophilia you have a reduction in factor 8 production which means or factor 9 production which means you have a tendency to bleed on the other hand we know with natural antithrombin deficiency these patients have a tendency to clot so what will happen if you rebalance a patient with hemophilia a by reducing antithrombin you are balancing the trotting so from one hand with the bleeding tendency on the other hand with a thrombotic tendency the slide now becomes balanced so that's the whole idea and that was the therapeutic hypothesis of using antithrombin targeting drug as i mentioned before safety first is our concern in all new therapies and we should think about not doing any harm so i'm going to move the goal pose now with investigational gene therapy trials so we talked about severe hemophilia a being those patients who have less than one percent we have mild hemophilia a whose levels are anywhere between five and above so patients with mild hemophilia a do not bleed as much now this is a this is a chart which shows that if you have severe hemophilia a i don't know whether i can show it by a marker but uh probably not but anyway as you can see when in in the x axis is the factor 8 value and in the y y axis is the number of joined blades so if you have severe hemophilia a you have a minimum of six or more blades per year as the factor rate level improves in a mild patient the inflection point is around 12 percent where there's hardly any bleeds so what we would like to do in a gene therapy goal for hemophilia is to actually have a sustained factor eight activities without the peaks and troughs that i talked about earlier with continuous expression and all we need is only twelve percent expression and that's enough to help the joints and to prevent blades so what we we also hope is that it is a single medical intervention that is we do the gene therapy once and it's a lifetime away from repetitive infusions of factorate i mean that would be the ideal for gene therapy so why gene therapy for hemophilia for researchers it is a perfect disease to study with this novel biotechnology it's a single gene defect with directly correlated phenotype meaning you know if you have a gene defect you have factor eight levels so it's directly correlated and the phenotype with severity you also know the amount of patient clinically how the patient behaves there is a wide range of benefit i can have five percent i can have 10 percent i can have 30 and it will still show benefit and even if i go up to 150 it's not going to cause any problems majorly for patients so there's a wide range of benefit for us and no tight regulation needed and the progress as you know although this is an old slide there have been many more gene therapies that have been licensed including lensmar and uh for sickle cell as well but of course sickle cell is ex vivo and for clinician patients in hemophilia as i mentioned it's a high burden in the current standard therapy there's a continued risk of mobility despite the giving factor eight there's always going to be some mortality and morbidity despite prophylaxis because we can never maintain a sustained factor rate level and also there is compliance variable variability and the cost of product and 70 of the world does not have access to clotting factor therapy in the way it should be and nor will they in the foreseeable future as i said as i already mentioned it is not a priority for most governments in the something in that 70 of the world market so we were the first group to publish in the new england journal medicine again um in 2011 this was on and you know associated virus vector-mediated gene transfer in hemophilia b so as i mentioned here dr tatnam who is a closer associate of mine and yours truly were part of the publication and we proved that we this was a seminal paper and no never before have we actually seen such fantastic results in patients after gene therapy with hemophilia and it was actually a sustained response in these patients so the continuum of gene therapies i wanted to talk about because they have been different approaches in different conditions and they have different application implications for efficacy safety and success so the gene therapy that i'm talking about is actually where the gene is then given intravenously it goes into the liver it then produces the g the gene of interest that it protein of interest that the gene transfer has made available and it then relieves the patient with the disease so that is a simple gene therapy we are talking about where we just infuse the vector in this case it was av or arduino associated vector we have gene editing where you can actually edit the ish the the gene that is not right and put the gene of interest into that edited place corrects the flow of faulty gene as it were then of course we talk about cellular therapy where we actually where the transplants the whole cells where the cells themselves have to undergo gene therapy and then or editing and then be given back to the patient so that is the complexity in terms of gene therapies so i talked about av gene therapy which is what we do in hemophilia so we know the good gene in hemophilia a so we would take the gene this gene is then packaged into something you need uh this is the cargo so you have the cargo you need a transporter so the transporter in this case is aab adreno associated vector uh adreno associated virus and the various various stereotypes and this particular stereotype that we use will target the liver because we know that both factor 8 and factor 9 are produced in the liver so we want this gene to go into the liver we use the virus mainly because it then can access into the nucleus and then release the gene of interest and as the gene of interest is released into the nucleus it then starts to produce factor whatever protein that you're meant to make so we then published uh the av5 factor eight gene transfer as i said the 2011 paper was actually for factor nine we then uh published on factor eight gene transfer in semior hemophilia a this was in 2017. so this was again a seminal paper where we had some fantastic result and i'm just going to show you very briefly the phase one study results however we have now gone ahead with the phase three and i'm not i'm not going to show you any data on phase three it is very similar to the phase one study and although it is not licensed no hemophilia treatment gene therapy is licensed yet but i'm sure the licensing will come through very shortly so this was then followed by an editorial as well about a beginning of a cure or cure for hemophilia because there was a back-to-back paper on both hemophilia a and b with a variant called padua at this time and a cure for hemophilia was within reach so this was the the way the cassette the vector cassette walls where there is an inverted terminal repeat there is a promoter of the gene then the gene itself which is b domain deleted factor 8 and the inverted terminal repeats these are all packaged into the av vector or the av virus so that it can be given intravenously we give billions of particles of the virus into the intravenously to the patient prior to that we need to check whether the patient has previously had a v infection because if you have an infection you obviously cannot give the virus because you may then it may not be benefic beneficial however in certain trials we have used it as well and it has still proven to be of use but we do check for zero prevalence certainly in factor eight so i'm just going to go through a few of the slides few of the patients that were in the trial participant three four five and six as you can see there is definite inter-patient variability um the patient one and two were actually lower dose so they didn't achieve much factor eight so as you can see here in the on the right on the left side you have the factor eight values and for most patients the values as i told you 150 is also fine so quite a number of them had good values in uh in the patient however it started to drop and to come to almost good values and the only problem is that they all had alt which is um the liver enzymes did go up because we are targeting the liver the gene is being gene does go into the liver and the protein is being produced in the liver and also there is going to be some antibody that the body is going to produce against the autonomy associated virus which again will target the liver so there are multiple reasons why alt will go up as you can see this is the participant seven eight and nine as well so they all had some fantastic results with factor eight levels so as i mentioned talking about safety most of the aes were about ald elevation and was reported in 10 out of the 15 subjects so we had two cohorts 6 e 13 cohorts that's 66 e 13 6 raised to 13 per kilogram was what was given to these patients and the pklt range did go up and in the other cohort as well which was a low dose cohort also had significant rises in the alt so as soon as the alt went up we gave steroids so treatment with corticosteroids was well tolerated in all patients and most of them did not drop their factory aid levels very low so it was okay as i mentioned it was tolerated across all doses new subject developed inhibitors to factor eight no subject be true we are still following up after almost seven years of gene therapy and i still have my patients coming to see me in the in the trial in order to make sure that you know the safety as i said is so important and unknown unknowns we will only pick up much later and we haven't picked up anything to date um and most commonly across all subjects was alt alt elevation arthralgia because all of them are hemophilia patients but pain fatigue headache so not much really speaking all the patients were really reasonably okay so what is important is evaluating the dosing in gene therapy for hemophilia there is an inter program there are many clinical trials for gene therapy and hemophilia um so the inter-program variability indoors this is dependent on the on the zero press zero this whatever the depending on which type of uh aav that we used as a b 8 or a b 5 depending on that the dose is variable and also there is intra program variability of the levels that the patient achieve but these are biologicals and i suppose we can never come around to changing the intra program variability or the variability of response of course it is very important to understand how the dose relates to safety and in this case it was mainly the alt elevation efficacy in terms of its level of factor rate that you achieve and durability how long will the factor rate last is it going to be once in a lifetime in fusion so as i said evaluating safety in gene therapy for hemophilia we are doing zero prevalence we look at in india we've just i've just done uh 150 patients where we are looking at the zero prevalence rate of either ae 5 a b 8 and the capsule immunity we also will be looking at the amount of transaminitis in the various clinical trials that are going on going on steroid use or other immunosuppressive agents that are being used the other main concern is genetic integration so av vector doesn't actually integrate with the genome itself it sits on the side so it is an episome even even then there could be some integration into the gene which is which if it does affect if it does go and integrate in an area where there is a high likelihood of oncogenic gene then there could be potential um there could be a potential uh cancer so that's what we are looking for we haven't found any as yet so we are very good about that inhibitor formation has to factor rate antibody and of course the vector shedding from the body whether it is there in the blood it's there in the species in this in the urine in the semen so we look at vector shedding and it takes about five years before all the vectors go away how do you evaluate efficacy clearly factor eight activity level is one of the efficacy these are the ideal target levels that we want to achieve in the specific target population what is the secondary efficacy that we are looking at is how much factor replacement we have reduced the amount of annual bleeding rate that has been reduced and the quality of life so this is the kind of levels that we have seen is where um the you know the num the levels of factor eight that have been uh achieved in the patients as you can see the median mean and median is very good over 78 weeks danielized bleeding rate as i mentioned has also reduced significantly once it reached greater than five there was no bleed and the annualized factor rate usage once it reached greater than 5iu per deciliter there were no bleeds as well so no factor rate usage these are all adult patients will av gene therapy be available for children as i already mentioned av is a non-integrating form it forms an episome and some can be lost in the cell when the cell divides liver in children is rapidly growing and it is only at age of 12 that two-thirds of the adult liver is formed there is higher growth in infancy so you don't really want to give it in children because they will lose the gene of interest and the benefit and risk in children need long-term follow-up and the question of ascent consent and until we know much about this particular gene therapy i don't think children will be brought into clinical trials as yet as i mentioned there are a number of clinical trials ongoing and many more to come there's a very high cost gene therapy is going to be high cost because of the complexity of manufacturing there is high inefficiencies throughout there is high inter-patient variability there's a lot of unknown causes of why the transaminitis does occur we don't know much about children whether there's going to be non-aav based solutions that are required and whether gene editing may be of use is still questionable a little bit about the indian scenario so i have set up a clinical trials and research unit um at kj samaya super specialty hospital and research center in mumbai we are now our site is almost ready for gene and cell therapy trials sorry my spelling mistake there um we are working with a couple of companies to deliver on both gene and cell therapy in india we will be starting trials first soon during the course of 2023 for multiple clinical programs including hemophilia obviously which will be our lead program and i would urge you to get in touch if you want to know more about this and if you want your patients to be part of this as well so it's not just necessarily only hemophilia but do get in touch it's going to be a lot more exciting times even in india thank you for further for listening and i'm happy to take any questions thank you so much ma'am that was indeed a very nice lecture and good to know that there are so many trials and research going on to find the cure or for the management of hemophilia i would request our audience members if you have any questions please put up in the comments section also you can use the raise and option to come on stage and ask the question directly to map there is a question ma'am by dr neha if you could please elaborate on vector shedding part in evaluating safety in gene therapy well we like i said we we look at uh the vector shedding both in many of the body fluids we look at it in the saliva we look at it in blood if we look at it in serum urine and stone and we check on a regular basis but these are vectors which are not necessary whole viruses they are just bits and pieces of the vector okay all right other than that well we have no more questions for today i think the research thing uh it was well explained and i'm sure our audience has learned a lot like i said that much needed to be done in the field of hemophilia like we do see patients coming up even for i think thalassemia and i would like to thank you again ma'am thank you so much for taking out the time thank you so much for adjusting the time zones we do know you are in uk and adjusting it for us uh it was an honor for netflix to have you here we surely hope to see you again on this platform and big thank you to our audience members too for attending this talk thank you

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