Podcast 13 Transcript: Professor Amit Nathwani’s journey to create a one-shot haemophilia A cure

Nigel Campbell

Hello and welcome to the latest episode of the UCL Businesses Big Talks on Big Impact Podcast. UCL Business or UCLB is the commercialisation company for UCL, and this is where we meet amazing people bringing about positive change through commercialising their ideas and research.

Now today I’m joined by Professor Amit Nathwani from the UCL Cancer Institute and Dr Rick Fagan from UCL Business who have been on a 10-year journey together to transform the lives of people with the world’s first one-time treatment for severe Haemophilia A.

Now Professor Nathwani’s groundbreaking gene therapy research coupled with Dr Fagan’s commercialisation process have got us to this point here where this treatment has now been licenced for use in patients in the US and across the EU, potentially changing hundreds of thousands of lives.  Professor Nathwani, Dr Fagan, thank you very much indeed for joining me today.

Professor Nathwani, perhaps we could start with you. Can you start by telling us a little bit more about what severe haemophilia A is and how it affects people’s lives and what the conventional treatments have been up until this point?

Prof Nathawani
Yes, of course. Haemophilia is a rare condition that affects the blood’s ability to clot. It’s inherited and most people who have it are males because the factor 8 and factor 9 genes that are affected are carried on the X chromosome.

Patients who have a severe form of haemophilia are individuals where the levels of normal UH clotting proteins in the blood are less than 1% of physiological, and so in essence, they have no functional clotting protein factory to factor 9, whether it’s haemophilia A or haemophilia B. And in that setting, these individuals are prone to what’s called spontaneous bleeds. And by that, what we mean is there’s no apparent trauma. So, these people may be just walking and suffer a bleed in their joints.

These bleeds can occur unexpectedly, occur in hard-to-treat sites like in the brain or within the abdominal cavity, and quite often are fatal. Now current treatment for haemophilia A across the world consists of administering the proteins that are either isolated from blood or synthesised in the laboratory, so-called recombinant factor 8 or factor 9 proteins, and these have been life changing. They have converted what is otherwise a life-threatening bleeding disorder to one where patients can enjoy near normal quality of life.

The downside of these protein therapies is that factor 8 and factor 9 have a very short half-life. In other words, once you administer them (and they have to be administered intravenously) the protein disappears very quickly from the circulation, which is where it’s needed to protect from bleeding. And so, you have to give frequent administrations of these proteins and you can imagine because it’s given intravenously, this is really very invasive, very demanding, and also very expensive.

The lifetime cost of haemophilia in the UK, haemophilia A or B is in the tens of millions of pounds for the lifetime of the patient; so, it’s very expensive treatment. And even with all of that effort put into treating patients, a significant number of patients continue to have bleeds. In other words, the treatment is not curative, it’s more palliative holds the process. And for those individuals, we felt that gene therapy type approach a one-and-done approach where you give the vector once, leading to endogenous expression synthesis off the protein, on a 24/7 basis for the lifetime of a patient, potentially would be the right solution. And this is what made us embark on our journey for creating these one-time opportunities for patients with haemophilia.

Nigel Campbell

I’m very interested in that moment when you realised that a radical new treatment was possible, was necessary. You’ve been at the edge of of treating patients because you’re the Director of The Katherine Dormandy Haemophilia Centre and Thrombosis Unit at the Royal Free in London. So, you know, you’ve seen thousands of patients. Well, can you remember a moment when you thought there must be a better way?

Prof Amit Nathwani

So, you’re quite right that patients are often the inspiration to developing new therapies but actually, the eureka moment occurred when I was doing research in blood coagulation, working with Professor Ted Tuddenham.

In those days we were basically using electroporation to introduce a bacterial gene into human endothelial cells.  These are cells that line our blood vessels, and we were doing it very successfully and it made me realise that, look, if I can put in a bacterial gene, then why the hell can I not put in a, pardon the pun, can I not put in a therapeutic gene?

Because that would be much more meaningful for treatment of patients and really what we were trying to do at that time (or thinking about doing) is to emulate the success of vaccines, which you know globally have had a huge impact on saving lives.  A single administration of the measles vaccine for example, could protect individuals for their lives, for the lifetime of those patients. And so that’s what we were trying to achieve with gene therapy that if we could have endogenous correction and expression for a genetic disorder, that would transform the lifestyle of patients and would make a difference, not just in the Western world, but also in the developing world where you know clotting factors, protein concentrates are unaffordable because of the lifetime costs associated with it.

Nigel Campbell
As you say whichever way you look at it, a potentially an amazingly transformative new therapy.  In simple terms if you could explain to someone like myself, who is not an expert, how does the gene therapy, the Roctavian treatment work as a one-off infusion to treat haemophilia A.  From what you’ve said so far, it’s a gene replacement vehicle, I understand.

Prof Amit Nathwani

Absolutely. So, basically what we’re trying to do is substitute for the abnormal gene that an individual has inherited. And so, we basically add into the cells of that individual, a normal copy of the gene that is fully functional, produces normal functional clotting factor, and so the challenge is how do you deliver that to that, that normal gene to the right cell.

And so, we thought a lot about this, and we learned that viruses have evolved over time to carefully and selectively release their payload in the target cells. And so, we decided that actually we would use nature’s gene delivery vehicle, which are viruses, essentially modify them to make them safer so that they don’t cause the viral infection, but use their ability to deliver the gene, to deliver the normal copy of the factory gene.

And so, we used a virus called Adeno associated virus. This is a very small virus. I sometimes feel God created AAV, as I call it, for gene therapy of haemophilia (not really the case because it’s also used for other genetic conditions), but it works really very well. It’s non-pathogenic.  So even when you get an infection with AAV, wild type AAV without genetic modification, it doesn’t leave behind a long-term sequela; doesn’t cause any abnormalities.

We modified, we put in the normal factory gene into an AAV. It’s given as a simple infusion, very much like a haemophilia patient injects their clotting factor. This is essentially an infusion that lasts an hour. The virus is clever. It makes its way to the liver where most clotting factors are made, releases the payload into the liver cells and it stays there, not embedded within our chromosomes, within the chromosome of the patient, but predominantly outside of the chromosome of the patient, which is an important safety advantage. And from there, it can drive the synthesis and expression of factor 8 levels that essentially protect patients.

Dr Rick Fagan

I think you’re being a bit modest, Amit. It wasn’t as easy as just taking the wild type Factor 8 gene and putting it into the AAV virus because AV viruses have, if we call the gene the payload, AV viruses have a certain amount of payload that it can take, and the factor 8 gene exceeds that payload limit. So, Amit and his research team had to do a lot of tinkering in order to basically pare down the gene whilst keeping it it’s activity. It wasn’t easy

Nigel Campbell
It’s an extraordinary amount of extremely technical cutting-edge research to get to that point. But of course, here we are 10 years on. As I mentioned at the beginning, patients have now started receiving this in areas of the world where it’s been licenced.

But there’s a huge journey to go on from the lab to the market like that. And as director of BioPharm at UCL Business, you know, you specialise in that commercialisation process for advanced medical therapeutics.  It’s notoriously challenging to get from the lab to the market. There’s so many hurdles. When did you first come across Professor Nathwani’s research and what did you feel about its potential at the time?

Dr Rick Fagan

Well, but I could say it’s been longer than 10 years. I’ve been working with Amit for nearly 20 years. I joined in 2006 and Amit was certainly on my radar, and probably back in 2009, he and I started working kind of exclusively together. Not just the excellent science but a very entrepreneurial nature to Amit.

He knew a lot about commercialisation, patenting, very engaged with ourselves, and you know, I think some of that probably came from the stint that he had at Saint Jude Children’s Research Hospital in Memphis, TN where he was involved in developing another gene therapy for haemophilia B, not A, which is factor 9 related haemophilia and was involved in the commercialisation process there as well. But of course, we do it much better here, don’t we, Amit?

Prof Amit Nathwani

Absolutely.

Nigel Campbell
How do you initially go about assessing whether medical research has kind of got what it takes to go the distance, Rick? What’s the sort of process that you go through to it to assess whether it’s got what it takes.

Dr Rick Fagan

So, you know, we’re a technology transfer organisation working with academics like Amit and himself. In academia, you must publish, and regards to that, we end up filing patents much earlier than say, if I worked at a company like BioMarin. They would wait much longer to file a patent. What we see, Nigel, is very early, really pretty early-stage technologies and we just have to take a punt, and we’ll file a patent. Many will fail, few will succeed, and even fewer will return significant revenue.

Working with someone like Amit, it’s easy because he just doesn’t talk the talk. He walks the walk as well, you know.  He delivers. So yeah, it’s a no brainer when Amit tells me “I’ve got something new, and we should talk about it” etc. In tech transfer world, we do end up finding many patents very early and many of which got nowhere.  So, there isn’t a crystal ball that I can look into and say this is going to make it, unless we are filing a patent at the point where say we had some Phase 1B clinical trial data and it looked very good etcetera. Then I might just say, yeah, I think this one’s probably looking good.

Nigel Campbell

You mentioned BioMarin, the company that licenced the technology and conducted the clinical trials. Can you tell us a bit more about that collaboration with them because that’s been a long journey as well, hasn’t it?

Dr Rick Fagan

Yeah. So that itself was 10 years. So, in 2009, we filed the first patents with Amit on the Factor 8 gene therapy and then another in 2013. And simultaneously with that second patent filing, Amit and his team published a paper in a very high-profile journal. It was ‘Blood’, was it not, Amit?

Prof Amit Nathwani

Yes, that’s right.

Dr Rick Fagan
…which showed that this, this, this new configuration of the factor 8 gene in the AV vector had very positive results in models of haemophilia and animal models of haemophilia. So, we had to, sort of, in vivo proof of concept which looked very promising and that sparked the interest of a number of companies; one of which was BioMarin. We engaged with them and in 2013 we ended up licencing to them the two patents, and you know they’ve been in excellent partner so far and I’m sure Amit will agree.

What we licenced to them was a preclinical asset in 2013 and in 10 years they took that all the way through the whole clinical trial process and got it to marketing approval is really a testament to them, That’s very, very fast. Yeah, they really put a lot of effort behind it.  We like them so much, we’ve licenced in 2019 another one of our technologies, not one of Amit’s, different professor to BioMarin and they progressed that into the clinic right now. So, they’re really a good partner to work with.

Nigel Campbell
I mean it it’s notoriously a rocky road going through clinical trials. What was there a moment, Professor Nathwani when you knew it was this was it, that was it. It was actually going to go all the way and make it to market.

Prof Amit Nathwani
I think we got an impression pretty early on when we did animal studies that showed that we were seeing nice levels of expression that would be protective in humans, and that these levels of expression were sustained force for many years, years of follow-up of those animals.

So that essentially gave us the confidence based on the fact that we’ve done this before with haemophilia B and you know, the clinical phenotype for haemophilia A & B is very similar, is identical. In fact, you know, gave us the confidence that look you know that this is this is likely to work, but you never know until you do the clinical trial. And I have to be honest that the clinical trial data for haemophilia A is marginally different from that for haemophilia B, which we would not have predicted from the animal studies.

Nigel Campbell
And so come last year, 2023, a huge pivotal moment when the treatment was licenced first in the US and then shortly after in the EU for use in patients…

Dr Rick Fagan and Prof Amit Nathwani

Other way around. It’s the other way around.

Nigel Campbell

Oh, sorry, I apologise. It was EU than the US. How did you feel when those approvals were confirmed? That was a big milestone,

Prof Amit Nathwani

Absolutely phenomenal milestone.  Humbling is, is the way I would put it because as clinicians, or clinicians/scientists, we all want to be involved in drug discovery, drug development. But it’s not often that you can take a drug all the way through to market approval so that many more patients can benefit from the discovery, the innovation. And yeah, it was great.  It was fantastic to see that this was now available on the market and many more patients would benefit from the impact of gene therapy for haemophilia. And so, yeah, exciting.

Dr Rick Fagan

I agree very much. I mean, yeah, very, very few people see a medical treatment they’ve worked on make it to market, just because of the fact of the nature of the business. It’s the, oh, it’s, it’s very, very risky. It’s riddled with failures etc. Even fewer have seen been involved in (a) the invention, making the invention (b) patenting, and then seeing it getting all the way to the market. I feel privileged, and I think it’s just really exciting for Amit, for UCLB, and for UCL to get this important treatment on the market.

Nigel Campbell
And I guess that also fires you with hope and enthusiasm with some of the other similar and unrelated technologies that are going to solve some of the big medical challenges of our time, right?

Dr Rick Fagan
Hmm, yes absolutely. You know, I think, you know for me, the next exciting thing in gene therapies, it’s probably currently what we’re talking about like haemophilia, they’re what’s called monogenetic diseases. There’s only one gene involved in the aetiology of the gene.  Many diseases like cancer or asthma or whatever, have multiple genes involved in the aetiology of the gene of the disease. Not always the same, Different, different people… I think it would be very exciting to see gene therapy now enter the realm where they start tackling some of these more complex diseases.

Nigel Campbell
And Professor Nathwani, the first patients as we’ve said, now being treated in both the US and the EU overall, what are your hopes for the future for this treatment for haemophilia A and indeed the treatment for hundreds of thousands more people around the world with the condition?

Prof Ami Nathwani
So you know we are at the beginning of the journey for gene therapy for haemophilia. It’s great to see that it’s available on the market and adults can be treated. We want to make sure that it’s available to everyone in the world that has haemophilia A.

We also want to make sure that ultimately this treatment moves from being focused on adults to also being available to children. And that would make a huge impact because many of the patients that we treat with gene therapy already have damaged joints as a result of recurrent frequent bleeds. And that’s not something we can change at this late stage. But if we started gene therapy early in children, then it would be possible to avoid these lifelong disabilities that many of our patients suffer and endure and it would make a big difference to the haemophilia community,

Nigel Campbell

It’s a wonderful prospect and such an exciting future ahead. A wonderful way to finish as well. Thank you, Professor Nathwani and Dr Fagan, so much for your time today. It’s been an absolute pleasure. Thank you too for listening. And if you’ve enjoyed this discussion, do look out for our other episodes of Big Talks on Big Impact wherever you get your podcasts. Until next time, thanks for listening and goodbye.

Dr Rick Fagan
Thank you.