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Gene Therapy Interview with Dr Michiel Coppens

On 14 May 2024 we were fortunate to have Dr Michiel Coppens join us at the HFA office for an interview about gene therapy.

Chaired by Dr Stephanie P’ng and led by questions from the community, Dr Michiel Coppens explained what gene therapy is, how it works, and how it can be used to treat people with haemophilia.

Dr Coppens draws on his extensive knowledge of haemophilia and experience in gene therapy – he dosed the first Dutch patient with gene therapy back in 2015 – to provide answers that are both thorough and easy to understand.

Gene Therapy: ‘Ask me Anything‘ with Dr Michiel Coppens

  • Dr Stephanie P’ng
    Haematologist, HTC Director, Fiona Stanley Hospital, WA
  • Dr Michiel Coppens
    Haemophilia Medical Specialist, Amsterdam University Medical Centers, Amsterdam, The Netherlands

HFA Gene Therapy Snapshot Survey

Do you, or someone close to you, have haemophilia?

Do you have 5 minutes to spare to tell us your thoughts about gene therapy as a treatment option?

HFA would like to understand what our community members want from their haemophilia treatments and your perspectives on gene therapy in particular.

Please complete the survey by Sunday 7 June 2024.

This survey is a snapshot of community attitudes and we would really value your feedback. It will help us to represent the community and may be used in our treatment advocacy.

You will find more information on the survey introduction page.

Gene Therapy Snapshot Survey

Video transcription:

Dr Stephanie P’ng:

Welcome to our interview on gene therapy. My name is Stephanie P’ng, and I work at the adult haemophilia treatment centre at Fiona Stanley Hospital in Western Australia.

Gene therapy has been in development for many years, and in Australia we currently have both haemophilia A and haemophilia B products in their final stages of clinical trials and progressing through the TGA process.

There are many questions from our community, and today Dr Coppens will first talk about what is gene therapy and how it works, followed by a question and answer session of all the questions you have sent through, and thank you for that.

Let me first introduce Dr Michiel Coppens, who is a haemophilia medical specialist at Amsterdam University Medical Centre in Amsterdam and in the Netherlands.

Dr Coppens was trained in internal and vascular medicine at the University of Amsterdam, and continued as a medical specialist in mainly thrombosis and haemostasis for over ten years within the Amsterdam University medical community. He is the acting head of the EUHANET and ERN EuroBloodNet certified Haemophilia Comprehensive Care Centre.

His current focus of research includes gene therapy for patients with haemophilia A and B.

In 2015, which was a long time ago now, he dosed his first Dutch haemophilia patient with gene therapy and has since then dosed a total of nine patients across different trials.

He is a member of the EAHAD working group on gene therapy, and is an author of over 150 publications.

Thanks very much for your time.

And now I’ll hand it over to Dr Coppens.

Dr Michiel Coppens:

Thank you, Dr P’ng, and thank you all for having me here.

Dr Michiel Coppens
Dr Michiel Coppens

I’m here in Australia, for a week, basically to do a lot of lectures about gene therapy. And, it’s an interesting and relevant time right now, because these therapies are really hitting our clinics and will be entering our clinics. So it’s really time to get ready.

In the first part of this interview, I will be doing a short presentation, basically laying out what gene therapy is and maybe tackling upfront some of the questions you may have.

Yes, I see that we are sharing. Well, as I said, ask me anything. There was a call to put in questions for me here. There have been, a number of questions and we’ll try to address most of them, but for now I’ll just start right ahead.

So I’ll start sharing my screen right now (and waiting a few seconds because usually there is some short delay.)

Yes, I see that we are sharing. Well, as I said, ask me anything. There was a call to put in questions for me here. There have been, a number of questions and we’ll try to address most of them, but for now I’ll just start right ahead.


As always, there are, disclosures. We collaborate with industry. There would be no gene therapy without the finance of industry. So there is an obvious need to collaborate. And I do so as well. However, these funds do not go into my own personal pocket. They all go to my institute.

Why now?

So why now, as I said, well, 22 to 24, we’re seeing globally the first regulatory approvals of AAV gene therapies for both haemophilia A and B. Dr P’ng already mentioned, where it started for me was already back in 2014 when the preparatory work started. And it actually it started with Amsterdam Molecular Therapeutics, which was a spinoff company of my hospital, which later became uniQure. And that’s the company that developed Etranacogene dezaparvovec, that became Hemgenix. And that’s the provisionally approved haemophilia B gene therapy now in Australia. And I’m here, as Dr P’ng said, because I have some experience there.

Where it started for Dr Michiel Coppens

I have dosed nine patients in haem A and haem B in different trials. And what you see here on the right, of course, in Dutch was a bit opportunistic. But in January 2016, we were proud and happy to be able to report that we were the first centre to actually dose a patient with haemophilia B gene therapy in the Netherlands.

AAV Gene Therapy: the basics

So I’m going to start with some basics. For some this will be already known, for others probably not. So I’ll work through the basics of proteins and gene therapy.

Essentially, the clotting factors, clotting factor VIII (8) and IX (9) are a protein. And proteins are essentially long chains of amino acids built into peptides. But this chain is then folded into complex, three dimensional structures. And that’s actually the protein. So, and the code for proteins are genes.

Essentially the genes are or contain the codes for the specific sequence of those amino acids and proteins. And all of those genes are located on the human chromosomes. And as you can see in the picture below, there are a huge number of chromosomes. But the genes for clotting factor XIII (8) and clotting factor IX (9) are on the so-called X chromosome, which makes severe forms of haemophilia predominantly a male disease.

Essentially, the liver is responsible for the production of most of the proteins in the human body. On the left hand side, you see a human cell. And essentially most of a human’s cells have exactly the same machinery. Machinery that is able to produce protein. The liver does the bulk of the human protein production, but essentially most cells have those machinery in place.

So essentially gene therapy is about to feed the, this cell protein manufacturing machinery, the protein factories, feed them the right code of the missing gene. And then that cell is able to generate that missing protein.

That’s the basis of gene therapy.

However, the big problem is, how do you get that DNA, that missing DNA into cells? Because most things you will do to cells will actually destroy the cells, and they will not be able to produce protein.

Well, that’s where we, where nature comes in.

There is a specific organism that is able to enter cells smoothly. And those are viruses. Viruses we all know and you see them on the left hand side. So essentially gene therapy is about using the outside of a virus that is enabling it to get into the cell and the inside of the virus is actually replaced by the gene of the missing protein factor XIII (8) or factor IX (9).

And here you see how that looks like. The AAV capsid, the capsid is the outside of the virus, which enables it to pass into the human cell with a gene cassette. That’s the DNA of the missing gene. And those combined is what we call AAV gene therapy.

AAV, what is that? That is an Adeno Associated Virus.

That’s a specific type of virus that is generally used in most gene therapies and in all haemophilia gene therapies.

Why are we using AAV viruses? There are some very important aspects. What you see on the left hand side is that the DNA that is entered into the human cell by an AAV virus is placed so-called episomally, it’s essentially non-integrating. Integrating would mean that the gene is actually put into one of those chromosomes.

The big sort of X thing you see, and would be inserted in there, and that actually contains a certain risk. And that’s, what I call fatal integration. What if that gene would be placed right in the middle of another gene that is actually quite important to the human body, or maybe what we call a tumor suppressor gene, if that gene is wrecked because something is put in there? That may lead to what we call fatal integration. And that’s always a sort of a risk thing.

And that’s the most important thing. Why we’re using AAV is that it’s largely non-integrated.

The other benefit is that it’s hardly immunogenic. Natural variants of AAV may cause a cold, but just as likely you will not experience any symptoms at all.

However, there may be some downsides because of this episomal localization of the DNA. When a cell divides into, proliferates and becomes two offspring daughter cells, the DNA that it’s placed episomally may actually not be transferred to all the daughter cells. So that means if you have episomal DNA, it may be lost over time, inherently.

And essentially ten years ago when I started the gene therapy, that was my primary assumption, that episomal DNA will be lost in due course over time.

The other downside is that you may have been in contact with the natural variant of that AAV virus. That may, or may not have, induced slight flu symptoms, but as a consequence, that will mean that you have antibodies to that virus. And if you have already antibodies against the natural variant of the AAV, the fear is that it may not work when you use this gene therapy, because it’s essentially already being broken down by your immune system before it’s able to affect your liver cell.

Current status of gene therapy in Australia

So what’s the current status in Australia?

On the right side, you see the first gene therapy for haemophilia B, Etranagocgene dexaparvovec. The brand name would be Hemgenix. That’s the one where there is now provisional approval for in Australia.

And on the left hand side you see the first gene therapy for haemophilia A, already approved in Europe and in North America, and that’s called Valoctocogene roxaparvovec. Roctavian. That is, they have filed for approval in Australia and it’s currently under review.

Gene therapy trials for haemophilia: what are the results?

So starting with the results, the haemophilia B, the Etranacogene dexaparvovec trial included 54 patients in total. And they got a single infusion of a thousand billion genome copies, gene therapy particles,infused in a single infusion over one hour.

So what happens then? Those virus, those are the virus particles, infect the liver cells and donate the missing DNA to the cell nucleus. And the liver starts producing protein.

Here you see the haemophilia B trial. And what you actually see is that the factor IX (9) activity goes up to an average of 40%. These were all patients with- that started with a factor IX (9) activity of 2% or lower. And that on average they move to 40%.

However, what you also see is error bars. Those are the bars coming out of those bluish boxes. That means there’s also considerable spread. Some people end up slightly lower, more or less 10% or lower, and some people lined up in the really higher end. And at this point we are not really sure what determines what level you will be reaching. So that’s always sort of a question mark. How high will you go. But on average we see 40%.

The most important thing to appreciate from this slide, because this is a three year follow up, is the apparent stability of the factor IX (9) expression achieved here. People get up to their factor IX (9) activity actually somewhere between week four and month six. And that’s probably more near the week four than near the month six. We see at month six and then it remains almost completely stable thus far throughout the complete follow up.

The farthest follow up thus far has been for three years.

So then moving from haemophilia B to haemophilia A, there’s a slightly different picture. First I’ve talked to you about the error bars, what you’re seeing here. And now you’re also seeing error bars here. But they are considerably smaller. But that’s a mis-, sort of a misrepresentation. You know, this is, these are slightly different error bars. And the variability of the expression is actually significantly larger than in the haemophilia B.

The range of factor XIII (8) levels you may end up with is quite high, varying from almost 5% to well over 100%. The average though, averages at around 50%. However, what you can also clearly see, and that’s the contrasting picture with haemophilia B, is that there’s a peak effect.

And that peak effect is around the six month mark. And then it seems to be going down.

And a big discussion thus far is, is this going down? And will at some point it end, leading to a full loss of expression, or does there remain a proportion of patients who will have sort of a sustained, stable level over time?

And essentially this is the four year follow up there has been thus far and been quite recently presented at a summit in North America. And this is the numbers you’re seeing.

Four years, there are still 16% on average factor XIII (8) activity. Yeah.

So what does that mean for a patient, if your factor XIII (8) or IX (9) activity goes up.

Well the simple point and the primary goal, I think, for gene therapy is that almost all patients can stop prophylaxis. However, you should also be aware that it’s just not a cure. Most patients will not end up in a normal factor XIII (8) or IX (9) range. They will end up in a milder haemophilia range, but that still means that they have a milder form of haemophilia, so patients will need additional factor XIII (8) or factor IX (9) when they undergo surgery or when they have a serious trauma.

What we’ve also seen is that people in these gene therapy trials have less bleeding and significantly less bleeding. About 60 to 70% reduction in bleeding. And that’s even compared to regular intravenous factor prophylaxis and, especially when your factor activity is somewhat in the higher ranges, that may give you also more leniency to do high risk activities, without having to worry too much about getting a bleed.

There is something new that’s been coined by several colleagues of mine in Europe, and that’s something that’s called the ‘haemophilia free mindset’.

And to some extent, that’s an interesting concept, but that, there’s a sense of we have seen anecdotal stories of patients who have, well, changed, more or less changed, having to think about the disease. It’s getting their disease, getting through the background more or less, and having a free, well, haemophilia free mindset.

And I think there’s wonderful anecdotal stories of patients who have experienced that.

However, at the same time, we should also realise that not all patients are getting to the real high end.

So the primary goal is to get rid of the prophylaxis and hopefully get high enough to be able to sustain some form of damage or some form of trauma.

Gene therapy: what don’t we know yet?

However, when we talk about, a once, irreversible therapy, it’s just as important to focus on what we don’t know yet.

And there is stuff we don’t simply know, yet. And that’s what I want to talk you through.

The big and first question, the number one question that tops all of them is simply how long does it work?

I’ve just shown you on the left hand side that in haemophilia A there is a peak in the factor XIII (8) activity at about six months and a decline thereafter.

And the big question still is, does it level out at some point to a lower factor activity, or will it wear off at some point and will all expression be lost?

How long will that take?

Well, it’s hard to say. 3 to 5 years maybe? I don’t know, maybe longer. And, for some patients we have seen in the trials, also sometimes shorter.

If we flip the perspective and look at year three of follow up in the studies we’ve seen in the haemophilia A study that13% of patients had to go back on prophylaxis because of progressive loss of expression.

On the other side, haemophilia B. As I said just now, it looks quite stable. But what does that mean? How long will it last? Well, we need to realise that this registration study, the maximum, published follow up, has only been three years, so we don’t know for the most patients, much more experience than the three years.

However, before you get to a registration study, there’s always a phase one study, as we call it. Less people, ten in total. But that started quite a while back. And for those patients, we now have a follow up of 5 to 7 years. But that’s, and also in that study, 5 to 7 years, quite stable expression over that full period of time. And there’s one and I think that’s the landmark, the frontrunner study in haemophilia B, that was from the UK University College of London. And they now have over ten years of follow up.

And similarly, as in this, the other haemophilia B trial, we’ve seen a very stable expression of factor IX (9) there. So there is hope that it will get you expression more than ten years. And some optimists, and I wouldn’t dare go as far, but some optimists say that it even may be persistent and ongoing.

If we also here flip the perspective and look at year three. At year three, there has been now one patient who has had to go back on prophylaxis in the haemophilia B trial, and that’s 2% of the trial population.

The other point is a rise in liver enzymes, generally called ALT. That’s the most common side effect of gene therapy. And typically this occurs within the first 12 weeks after the gene therapy administration.

In the very, very, very early phase of studies on gene therapy, there was quite a clear case where it was shown that this ALT increase was caused by an immune reaction specifically directed at the liver cells containing the gene therapy.

So, in effect, your immune system would recognise the cells that have had gene therapy and specifically attack those cells. And if that happens, that can lead to a loss of the factor VIII (8) or factor IX (9) activity. And again, in that front runner study in the UK, they decided to really monitor the ALT levels. And as soon as they got up people were treated with the immunosuppressant prednisone and actually that worked. But, and simply because it worked, it became the norm for all the gene therapy trials thereafter.

And again, we’re seeing differences between haem A and haem B.

On the left hand side in the haemophilia A trial, we see that around 80% of participants, of recipients of haemophilia A gene therapy had developed ALT rise and had to go on corticosteroids.

The good side is that maybe due to that prednisone, there was no further loss of factor VIII (8) activity with that ALT increase. However, there is a price to pay because the average duration of prednisone therapy was six months, and that’s an average. There were people the short space of three weeks, but the longest period was well over a year, 18 months. So that’s quite a long time.

And prednisone may be a therapy that will give you side effects. Most people will notice when they are on prednisone. So there is a price to pay.

In haemophilia B also some people develop ALT, but the prevalence is much lower. And it was 1 in 5 patients had ALT increase and had to go on prednisone. Again, also there the prednisone at least seemed to prevent any loss of factor IX (9) activity. And the total duration was still quite long, but shorter than in the haemophilia A, three months with a spread of 1 to 4 months in full.

The other thing I talked about, already in the introduction, is that you may have been in contact with the natural variant of that AAV virus. And that’s what I call pre-existing immunity against AAV, because in response to that infection, you will have developed antibodies against that particular virus.

What we know from surveys is that approximately, we should expect 25 to 35% of people who have been in contact with that AAV virus and to have antibodies. And generally it had always been presumed that if you give a patient gene therapy, before that gene therapy is able to successfully infect the liver and donate the factor XIII (8) or IX (9) DNA, it would already be eliminated by your immune system.

However, there was a sort of a lucky error in the haemophilia B study. In the first phase study, during the study, the first ten patients, they actually switched an assay. And it turned out that in hindsight, three of the patients that they dosed already had AAV antibodies. And to their surprise, they expressed factor IX (9) as well as those without antibodies. And now it has been fairly well established that in this haemophilia B study, it works as well in patients with low titre antibodies, as in patients without antibodies. They are tested, as a screening part, but it’s not an exclusion criterion for haemophilia B.

In haemophilia A, similarly, we should expect 25 to 35% of patients having these antibodies. And in the haemophilia A study at this point, if you have preexisting neutralizing antibodies, you are ineligible. So if that titre comes back positive, you cannot get this gene therapy.

Similarly, there are now studies ongoing for patients with haemophilia A that have antibodies to see if, like in haemophilia B, those antibodies would not be problematic. But until there is positive evidence that you can actually dose those patients, you are completely ineligible if you have neutralizing antibodies in haem A.

So, long term effects.

If we’re doing a once irreversible therapy, what about the long term? You really have to wait long to see long term effects. I told you the biggest benefit of the AAV is that it’s a so-called non integrational localization of the DNA. However that’s not fully true.

‘Non integrational’ means that less than 0.5 percent integration occurs.

But if you are treated with a thousand billion genome copies of gene therapy, some integration will occur. And there, so there’s always been a theoretical risk of that fatal integration. And whether or not that could lead to liver cell cancer (excuse me for the typo here.) and in fact, in the haemophilia B study, one year after gene therapy, one person actually developed liver cancer. And I have to say, that was a person from my own centre. That was a patient I have, well, that was under my care in this trial.

Immediately we were aware that we needed to get to the bottom of this, whether or not this was caused by gene therapy, because if it were caused by that gene therapy, that could mean the very end of gene therapy for haemophilia altogether.

So in collaboration with a laboratory in Germany and the sponsor of the study, we did an extensive integration analysis, and we were able to conclude that this was not the complication of gene therapy, but actually we found a few mutations that were quite typical for patients who have had chronic hepatitis C in the past and could develop liver cell cancer as a consequence of a chronic hepatitis C infection, a very important one.

But as a consequence of this event, there is this ongoing, cautious approach that everyone who receives gene therapy gets a liver ultrasound twice yearly to monitor for any such effects.

Practicalities of receiving gene therapy for haemophilia

So moving into practicality.

Before gene therapy, there needs to be some screening. As I told you, the AAV antibodies need to be tested and if you have any for haemophilia A then that’s where the story ends. For haemophilia B, depending on the titre, you can probably go ahead.

The other thing that really needs to be monitored is to assess chronic liver damage.

Some patients may have had prior hepatitis C, which has been pretty common in the haemophilia community. But now, well, emerging epidemic pandemic is what we call fatty liver disease. It’s now the number one cause of liver transplants globally. So that’s an emerging disease. And patients who are already have significant liver damage are ineligible for gene therapy.

So that means you will need to undergo some testing. Blood works on the one hand and some form of imaging of the liver to make sure that there is no chronic liver damage.

The dosing day. Well, the dosing day really is a big day, to some extent. You know?

This is on the left hand side. You see Dan Breederveld, he’s a patient with haemophilia B. He was treated in the context of the haemophilia B trial and I’m showing this picture with his permission. He’s an occupational health physician himself. And this is the typical picture every haemophilia gene therapy recipient has – being there on the bed. And this is me, getting an infusion into his arm.

I say that’s a big day because the first patient I dosed – that was already nine years ago – I bring him each year to teach medical students, and he always remembers the particular date on which he received gene therapy. As much as he remembers his, the day of his marriage.

So this is a very instrumental big day in a person’s life.

From a doctor’s perspective, and maybe also from a patient perspective, it’s not that big a day at all.

You come into the hospital, you get an infusion, which is usually uneventful. That infusion takes about one hour.

However, you are more, longer in hospital than one hour. We actually do not let the pharmacy prepare the gene therapy until you are actually there. What if you trip before entering the hospital and cannot receive gene therapy? With a product that’s hugely expensive? We just don’t want to run that risk. So people come in a few hours early.

And also in protocol, as I’ve heard in Australia, that they are planning out. That means after, or observationally, you will probably have an overnight stay at your centre just to be able to, if anything occurs that you’re in a place where you can get, immediate response, evaluation, etc..

So, approximately 10 to 15% of patients will experience mild infusion reactions that may be feverish, that may be chills, that may be discomfort. Those are usually pretty mild. Sometimes the infusion can be interrupted but can resume later at a slower pace. But most of the patients with these matters can sustain infusion quite normally.

In the first 24 hours or so, some people experience some form of flu-like symptoms – 10 to 15% – and personally, I think that may be a consequence of a sort of, mini AAV sort of infection. I had one patient who told me, I asked him the next day, how did you feel? “Yeah, well, I felt fine. Yeah, well it was a bit chilly when going to bed, so I just tucked in better in bed and then I felt fine afterwards, and I feel fine today.” But those kind of flu-like, very mild symptoms may also occur.

What I’m showing in the red, and there are different plans already being prepared or laid out by Australian treatment centres, is that it actually may be that -if you will be receiving gene therapy – that may not be in your own centre.

There are probably going to be centres that will be dosing centres. That has to do with all the environmental permits. You have to be able to do gene therapy. But the dosing day may actually not be in your own haemophilia treatment centre. Thereafter, all the follow up usually should be in your haemophilia treatment centre.

The follow up is quite important.

There’s a short term follow up, and this is probably one of the most important things to remember. You need to undergo weekly blood sampling for the first 3 to 6 months.

Why? Because we really want to see in time if you have an ALT increase, because if that ALT increase is caused by an immune response that leads to the loss of gene therapy, you need to go on prednisone, and that’s something that you need to plan in as one of the possibilities when you’re choosing for gene therapy.

If you need weekly visits for 12 to 26 weeks, even that can interfere with your holiday planning. And most of the patients I said, basically, so you probably can’t go on a holiday unless it’s really close by.

The other thing is condom usage. While, basically, the gene therapy does not go into your sperm cell, there is some shedding of the viral capsid, the outside of that virus, that will end up in your blood, that will end up in your nose, and also, also in your semen.

As a precautionary measure, the label says that you should use barrier contraception in the first year after gene therapy. So basically, if you’re really planning on children, not in the first year after gene therapy.

Alcohol. Well, basically, you need to be cautious with alcohol. Of course I don’t think it’s realistic to say that you can never drink alcohol to keep your liver in the best condition possible, but maybe in those first 12 to 26 weeks, you want to be really careful. What if a good night of alcohol would lead to a slight ALT increase on the next day of blood sampling? That will mean that alcohol will put you on prednisone, and prednisone can be 3 to 6 months. So be really, be careful with alcohol, especially in that short term period.

Once you’re through that phase, you go into the long stage follow up and blood sampling usually every three months. As I just told, twice yearly you will get a liver ultrasound, and essentially, I think that’s probably the way it works.

I think we’re going to want to follow up patients for long term and maybe even long, long, long term, for the rest of your life.

One of the, challenges, I guess, is, again, logistics. What if you don’t live near your haemophilia treatment centre, or if your haemophilia treatment centre is not yet experienced with gene therapy?

There are specific demands on logistics, on where do you get your blood sample drawn, how do you get those results to your haemophilia treatment centre? The Australian centres are already quite far in thinking about how to manage that. But again, there are some logistics on how that could work.

Positioning of gene therapy

So positioning of gene therapy, where will it be? Will it be a therapy chosen by everyone? No, of course not.

I think this is probably what we should be choosing. Clotting factors, intravenously, they have proven efficacy, proven safety over the years, and a lot of people will stay there.

Non factor replacement for haemophilia A is really, well, gaining popularity over the last recent years. And is, well, already, a new therapy with less treatment burden than frequent I.V. injections. So I guess this, thorough competitor of any therapies.

Other new therapies also emerging.

And finally, there is gene therapy.

And ultimately, I think, about gene therapy, probably if you look at the in and exclusion criteria, the eligibility criteria, and if we disregard the neutralizing antibodies as we can in haemophilia B, I think probably most patients will be suitable for gene therapy.

But then again, I don’t think everyone will choose for them.

Probably it has to do with who you are. So that’s something you really need to think about. You always have the persons that preordered the next iPhone way before it comes. Maybe those are the ones who have entered trials. But there’s also a group of people that just want to sit at the back of the bus and only wants to step in once it’s really, really proven.

So I think much of this is about how do you feel?

So essentially what you need to think about is about different scenarios.

What you should realize is that this is a sort of an irreversible treatment. Once you’ve done it, once you’ve had it, you can’t go back. The big, upside, of course, would be no more prophy, at least for a while. And hopefully for a very long while, you can expect a better bleed protection than you have had with your regular effective prophylaxis. But you need to balance that with potential downside. There is an intense follow up that you probably will need to adhere to. There is a chance that you will need to go on prednisone. Are you willing to do that?

Lifestyle? As I just told you, [limit] alcohol, especially in those first weeks. And barrier contraception for the first year.

And ultimately, that’s at the bottom right, there are inherent uncertainties about the durability, and always with new therapy, unexpected long term effects.

So essentially what it comes down to is that you need to make a trade off to the benefits you hope to achieve, and how much of uncertainty you are willing to accept to get those benefits.

And I think, yeah, actually, that was my last slide. So I’ll stop sharing there.

And let’s open the discussion with Dr P’ng.

Gene therapy: Q&A

Dr Stephanie P’ng:

Thank you very much, Dr Coppens. That was a brilliant presentation and I think very clear for the patient community. I think you’ve really nailed the kind of practicalities of, and the benefits, and the risks of it.

You touched on the durability. Some of the questions that came out from the community included what about the existing damage to my joints, will it improve that? Will it decrease it? Does it affect it?

Dr Michiel Coppens:

I think realistically, the joint damage, haemophilia arthropathy, as we medically call it, is irreversible joint damage.

So essentially, you shouldn’t expect your joints to heal when your factor VIII (8) level goes up or down. So essentially that’s part of the discussion, right. If the patients who are going to get gene therapy, ideally you want to get the gene therapy to them before they have already existing joint damage.

So I’m afraid that the joint damage really will persist.

Dr Stephanie P’ng:

And this is more of a theoretical question now, but do you ever envisage gene therapy in a paediatric population?

Dr Michiel Coppens:

Well, realistically, I think that’s the ultimate goal. But that’s still painting a far picture. A real far, far distant future.

The hard part about children is that they have growing livers. And growing livers means those livers proliferate, and in a proliferating liver, I’m not 100% sure that this AAV gene therapy will actually persist in a growing liver.

So probably that will take another form of gene therapy, maybe an integrating form of gene therapy.

But that needs to be safe above everything else.

So yes, that’s definitely the long term goal. But I think that we are years to, maybe even decades away from gene therapy in children.

Dr Stephanie P’ng:

Okay. Interesting.

So, the other question that came along from the community was, I guess they were concerned about whether or not they can have children after gene therapy.

And does the gene therapy actually affect the inheritance of haemophilia?

Dr Michiel Coppens:

Yeah, it’s an important question. Comes up a lot.

Essentially the gene therapy doesn’t do anything with your sperm cells. It really goes into the liver. So it means that your sperm cells still have, or still don’t have the correct haemophilia gene. So essentially your offspring will not be cured of haemophilia because you have had gene therapy. They will still have the same inheritance of haemophilia as usual.

As I also just told you, there is a reason to use barrier contraception for the first year. That’s not because we think that there is a real risk of your children within that year getting something. But that’s really a very precautionary measure. And after that year, yeah, you can have children. And there have been children from patients who have undergone gene therapy in the past.

Dr Stephanie P’ng:

You were outlining the benefits of gene therapy, and you were talking about decreased bleeding risks or decreased bleeding events, and a sort of surrogate marker of factor levels.

What about if they needed major surgery, for example, they needed their appendix out or gallbladder out at some stage, what happens then?

Dr Michiel Coppens:

Well, I guess it depends on what factor activity is actually achieved. If you happen to be a patient who ends up, let’s say, 70 or 80% factor VIII (8) or factor IX (9), then probably you are good to go for most types of surgery. But realistically, the transformation is to a milder form of haemophilia. It’s not a cure. So realistically you will have a milder form of haemophilia. So you need additional factor VIII (8) or factor IX (9) to safely undergo procedures.

Dr Stephanie P’ng:

And would it affect the risk of developing inhibitors later on?

Dr Michiel Coppens:

I don’t think so.

Please note that in the studies that have been done, they were quite selective and only including those patients who have really been experienced factor VIII (8) or factor IX (9) users. And we know that if you have had more than 150 days of factor XIII (8) or factor IX (9) infused then the chance you will ever develop an inhibitor will be really small. So generally, I don’t think there is a big risk of any inhibitor developing thus far.

In all the clinical trials, there has not been a single patient who had an inhibitor in development, as far as I know, that has been in Congresses, and publications.

Dr Stephanie P’ng:

Okay. All right.

You were talking about the side effects, and the use of steroids. Have you, separate from that, have you noticed any sort of unusual impacts on patients who you’ve given gene therapy to, in terms of their mental health and their overall image of themselves?

Dr Michiel Coppens:

Yeah. Well, generally it is really a positive picture, because most of the patients really move out of the severe haemophilia range through a much milder range, and they will have a much, much less severe disease.

So actually some of those stories are really powerful and beautiful anecdotes how it changed their lives. So generally these are positive.

But again, especially in haem A, there will be patients who have had success who have been off prophy that will need to go back on prophy. That will do something to you mentally, so that can be a huge blow.

Similarly, if you go into the screening process and you’re really set on getting this gene therapy, and then you are someone with neutralizing antibodies or have some preexisting liver damage, that’s a huge mental blow.

That’s some of the things you can see.

But for those successful, I think, well, more and more patients are now coming to conferences and listening to those anecdotes. And I’ve even had some of my patients come to conferences.

Those are really beautiful stories and generally very positive.

Dr Stephanie P’ng:

Have you ever had a situation with siblings [receiving gene therapy], where one has, and one hasn’t been successful?

Has it changed the family dynamics?

Dr Michiel Coppens:

Oh, I can imagine so.

I don’t have any particular examples. But yeah, sure, I could imagine. Yeah.

Dr Stephanie P’ng:

Okay. Just moving on to a few other questions that have come from the community.

One person asked whether, or not gene therapy would be suitable for patients with mild haemophilia?

Dr Michiel Coppens:

Essentially, technically it’s possible. And yeah, if you’re, moderate or mild, but in a lower, mildest range, I think there may be benefits for gene therapy. But ultimately I don’t think regulators will let it get that far.

The stupid thing is that you need to realize that this is very expensive therapy. And essentially that means that that will probably be licensed for patients with severe forms of haemophilia, that already need to use factor concentrates for prophylaxis. And prophylaxis costs a lot.

So there are some interesting financial trade offs to be made.

Personally, I’m afraid I don’t see it coming for patients with mild haemophilia, and probably it’s a cost issue.

Dr Stephanie P’ng:

Okay. Thank you.

I guess realistically as well, with gene therapy, maybe the people with mild haemophilia actually have higher levels in a way, than what has been seen in the gene therapy trials.

Dr Michiel Coppens:

Yeah. Well, if these new therapies are getting very successful then maybe the moderate haemophilia or the mild haemophilia with the lower ranges may become the more severe patients.

However, if you are a mild haemophilia patient and let’s say you are 15% or over in general, you shouldn’t have too much bleeding on an annual basis. So adding let’s say 10, 20, maybe 30% will not create a huge dramatic shift in the number of bleeds you will get on an annual basis.

So the difference is just bigger coming from severe haemophilia moving to mild than from mild to less mild.

Dr Stephanie P’ng:


Just shifting gears slightly, I guess one of the major unmet needs in our community are patients with type 3 von Willebrand disease and they, as you know, have very low or no factor XIII (8).

Would this type of gene therapy be applicable to them? Or can you envisage something else?

Dr Michiel Coppens:

Gene therapy, this gene therapy essentially not. Because basically patients with type 3 von Willebrand disease have a perfectly normal factor VIII (8) or factor IX (9) gene. So there is no point of it producing another factor VIII (8) or IX (9) DNA into their cells.

So the therapy will need to come from something different, and probably will need to come from von Willebrand itself.

Von Willebrand is a very big molecule, multimerization complex molecule. So putting that into gene therapy is more challenging than for haemophilia. There are well, initiatives, preclinical only, ongoing to also try to work gene therapy for von Willebrand disease. But as I said, significant challenges and thus far the most effective form of prophylaxis will be factor linked to von Willebrand itself.

But that’s still requires, at this point, frequent von Willebrand factor infusions.

Dr Stephanie P’ng:

Okay. All right.

Thank you very much for your time, Dr Coppens, I think that’s most of the questions covered. I will end here. Thank you.

Dr Michiel Coppens:

Well, thank you very much, and was my pleasure trying to help out the Australian community.

Dr Stephanie P’ng:

Brilliant, thanks.

Haemophilia Foundation Australia would like to thank Dr Michiel Coppens and Dr Stephanie P’ng for kindly sharing their knowledge and experience.

Important Note: This information was developed by Haemophilia Foundation Australia for education and information purposes only and does not replace advice from a treating health professional. Always see your health care provider for assessment and advice about your individual health before taking action or relying on published information. This information may be printed or photocopied for educational purposes.

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