Haemophilia is back in the news with the UK government being advised most strongly by Sir Brian Langstaff, in the Infected Blood Inquiry Interim Report, to issue immediate £100,000 compensation to the men, women and children treated by the National Health Service for conditions like haemophilia, who were given infected blood and infected blood products since 1970.
Haemophilia is a genetic disease where the person affected is unable to produce certain blood clotting factors which results in them being at risk of spontaneous bleeding and life-threatening haemorrhages. It is estimated that about 1 in 10,000 people are affected and the majority are male as the genetic defect is within the clotting factor gene located on the X chromosome. Most cases occur when the abnormal gene is inherited however about a third of cases actually occur in utero due to new mutations in the X chromosome and are not inherited at all… so you don’t need a family history of haemophilia to be born with haemophilia!
Remember back to your GCSE or O-level biology days when you learnt that humans have pairs of chromosomes and the X and Y chromosomes determine if you are male or female; XX female, XY male. Now if you have a dodgy X chromosome and you are female, your other X chromosome usually takes over and you are fine. However, if you are male, you don’t have another X chromosome you have a Y and so you are affected. In the case of haemophilia, the gene for clotting factor production is on the X chromosome and so a female haemophiliac would have to have a fault on BOTH X chromosomes to be affected, and this is very rare.
There are two main types of haemophilia, A and B. Haemophilia A occurs when the clotting factor affected is Factor VIII, haemophilia B occurs with Factor IX. The normal treatment for both conditions is three times a week infusions of the missing clotting factor; about 130-150 infusions per year… every year… for the rest of your life…!
HOLD ON! This is a microbiology blog, not a haematology blog, what is going on?!
Okay, stay with me, this is where the microbiology comes in…
Roctavian, is a new treatment for haemophilia
Roctavian, or valoctocogene roxaparvovec (what a mouthful!), isn’t a Eurovision entry but a new treatment for haemophilia based upon microbiology related gene therapy.
Roctavian is a form of gene therapy that delivers a new gene for the production of the missing clotting factor directly into the patient’s cells which then produce the missing clotting factor stopping the patient being at risk of bleeding. Simple?!
Well, it’s not that simple really…
The original trial name of Roctavian was AAV5-hFVIII-SQ… I don’t know what the SQ stands for but the AAV5 stands for Adeno Associated Virus serotype 5 and the hFVIII stands for human Factor VIII. The AAV is the clever, and microbiology, bit.
AAV technology uses a genetically modified virus-like particle to carry a new piece of genetic material to a target cell. The AAV then enters the cell and releases the new genetic material into the cell’s nucleus. The new genetic material forms an episome, a separate piece of genetic material to the chromosome, which can then be used to produce new proteins. In the case of Roctavian, the new protein is Factor VIII.
There is an animated video showing how this technology works on the website of one of the companies who produce the vectored virus here.
Does Roctavian work?
Well, it appears that Roctavian works very well. From the Phase 2 and 3 studies reported so far (called GENEr8-1… “Generate”-1?), following a SINGLE infusion of Roctavian, spontaneous bleeding was prevented in 85-90% of 134 patients with severe haemophilia A for over 2 years (this is how long the study has been running). A continuation of the earlier and smaller phase 2 study has shown efficacy continuing for 6 years in 13 of 15 patients. For each of these individuals, 1 infusion of Roctavian has replaced >800 infusions of Factor VIII and allowed them to live a normal life… that is amazing!
But what about haemophilia B? Well, a more recent study of a varied formulation of the AAV technology where the gene replaced is that for producing Factor IX has shown similar results with 70% of patients being bleed free after infusion.
It can’t be all wonderful, what are the drawbacks?
Okay, let’s get the elephant in the room out into the open… Roctavian is expensive! And I mean REALLY EXPENSIVE!!!! I saw figures that suggest that a single treatment with Roctavian will cost $3million MORE than the current Factor VIII treatment. This is the cost the company BioMarin will charge in order to just breakeven from development in 5-8 years. BUT if you have haemophilia, you’d think this was worth every cent… and I would agree 100%!
Another potential problem is that a person might already have antibodies against AAV5, in which case their immune system will neutralise the treatment before it has an effect. At the moment patients are screened for these antibodies before receiving treatment. It may be that in the future, different viruses could be used to deliver the treatment to get around this as the antibodies do seem to be serotype dependent, i.e. if you have antibodies to AAV5 then maybe AAV3 would work?
There are some concerns about the oncogenic potential of gene therapy, but it seems the risk is pretty low with AAVs. The new genetic material isn’t incorporated into the genome of the cell, it sits outside of this, and so it is not passed on to daughter cells during cell division. As long as this remains the case, it is very unlikely that the new material could trigger a cell to become cancerous. However, because there is a concern there is a 7-year safety study that is 6 years in and hasn’t shown any problems with cancer risk or severe side effects (compare this amount of safety data to the Covid vaccines we all lined up for which only had a few months of safety data!).
The final issue is around duration. It is unclear how long an infusion of Roctavian will last. The manufacturers estimate a single infusion will last at least 8 years which is pretty good. It’s a shame it’s not permanent but a single infusion replacing >1000 infusions has got to be a good thing! If the patient has antibodies to AAV5 unfortunately they can’t have the treatment. Added to this, once a patient has been given the treatment it is not known if this treatment will trigger the development of antibodies thereby preventing them having further doses and they would relapse. It is also unclear how long it would take for someone to produce antibodies because of repeat Roctavian infusions, for that we’ll just have to wait and see.
So, what next? Well, Roctavian has just been recommended for approval by the European Medicines Agency so it may become available in the EU very soon. I suspect the UK will follow as well, especially given the public disgrace the Infected Blood Inquiry is uncovering. The US are being a little more cautious in that they are waiting until the 7-year safety study has finished, but I suspect they will move pretty fast after that as it is the first time we have had a good and safe treatment for this horrible condition.
And here’s some more food for thought… we’re only just starting with this technology with haemophilia… this technology could be used for ANY single gene defect where an AAV is used to insert a correct gene into a cell… research is ongoing for retinal diseases, Alpha-1-antitrypsin deficiency, muscular dystrophies, Parkinson’s disease, Batten disease, cystic fibrosis, Alzheimer’s, spinal muscular atrophy, etc, etc… just imagine the potential benefits! Isn’t microbiology great? :-)
Remember back to your GCSE or O-level biology days when you learnt that humans have pairs of chromosomes and the X and Y chromosomes determine if you are male or female; XX female, XY male. Now if you have a dodgy X chromosome and you are female, your other X chromosome usually takes over and you are fine. However, if you are male, you don’t have another X chromosome you have a Y and so you are affected. In the case of haemophilia, the gene for clotting factor production is on the X chromosome and so a female haemophiliac would have to have a fault on BOTH X chromosomes to be affected, and this is very rare.
There are two main types of haemophilia, A and B. Haemophilia A occurs when the clotting factor affected is Factor VIII, haemophilia B occurs with Factor IX. The normal treatment for both conditions is three times a week infusions of the missing clotting factor; about 130-150 infusions per year… every year… for the rest of your life…!
HOLD ON! This is a microbiology blog, not a haematology blog, what is going on?!
Okay, stay with me, this is where the microbiology comes in…
Roctavian, is a new treatment for haemophilia
Roctavian, or valoctocogene roxaparvovec (what a mouthful!), isn’t a Eurovision entry but a new treatment for haemophilia based upon microbiology related gene therapy.
Roctavian is a form of gene therapy that delivers a new gene for the production of the missing clotting factor directly into the patient’s cells which then produce the missing clotting factor stopping the patient being at risk of bleeding. Simple?!
Well, it’s not that simple really…
The original trial name of Roctavian was AAV5-hFVIII-SQ… I don’t know what the SQ stands for but the AAV5 stands for Adeno Associated Virus serotype 5 and the hFVIII stands for human Factor VIII. The AAV is the clever, and microbiology, bit.
AAV technology uses a genetically modified virus-like particle to carry a new piece of genetic material to a target cell. The AAV then enters the cell and releases the new genetic material into the cell’s nucleus. The new genetic material forms an episome, a separate piece of genetic material to the chromosome, which can then be used to produce new proteins. In the case of Roctavian, the new protein is Factor VIII.
There is an animated video showing how this technology works on the website of one of the companies who produce the vectored virus here.
Does Roctavian work?
Well, it appears that Roctavian works very well. From the Phase 2 and 3 studies reported so far (called GENEr8-1… “Generate”-1?), following a SINGLE infusion of Roctavian, spontaneous bleeding was prevented in 85-90% of 134 patients with severe haemophilia A for over 2 years (this is how long the study has been running). A continuation of the earlier and smaller phase 2 study has shown efficacy continuing for 6 years in 13 of 15 patients. For each of these individuals, 1 infusion of Roctavian has replaced >800 infusions of Factor VIII and allowed them to live a normal life… that is amazing!
But what about haemophilia B? Well, a more recent study of a varied formulation of the AAV technology where the gene replaced is that for producing Factor IX has shown similar results with 70% of patients being bleed free after infusion.
It can’t be all wonderful, what are the drawbacks?
Okay, let’s get the elephant in the room out into the open… Roctavian is expensive! And I mean REALLY EXPENSIVE!!!! I saw figures that suggest that a single treatment with Roctavian will cost $3million MORE than the current Factor VIII treatment. This is the cost the company BioMarin will charge in order to just breakeven from development in 5-8 years. BUT if you have haemophilia, you’d think this was worth every cent… and I would agree 100%!
Another potential problem is that a person might already have antibodies against AAV5, in which case their immune system will neutralise the treatment before it has an effect. At the moment patients are screened for these antibodies before receiving treatment. It may be that in the future, different viruses could be used to deliver the treatment to get around this as the antibodies do seem to be serotype dependent, i.e. if you have antibodies to AAV5 then maybe AAV3 would work?
There are some concerns about the oncogenic potential of gene therapy, but it seems the risk is pretty low with AAVs. The new genetic material isn’t incorporated into the genome of the cell, it sits outside of this, and so it is not passed on to daughter cells during cell division. As long as this remains the case, it is very unlikely that the new material could trigger a cell to become cancerous. However, because there is a concern there is a 7-year safety study that is 6 years in and hasn’t shown any problems with cancer risk or severe side effects (compare this amount of safety data to the Covid vaccines we all lined up for which only had a few months of safety data!).
The final issue is around duration. It is unclear how long an infusion of Roctavian will last. The manufacturers estimate a single infusion will last at least 8 years which is pretty good. It’s a shame it’s not permanent but a single infusion replacing >1000 infusions has got to be a good thing! If the patient has antibodies to AAV5 unfortunately they can’t have the treatment. Added to this, once a patient has been given the treatment it is not known if this treatment will trigger the development of antibodies thereby preventing them having further doses and they would relapse. It is also unclear how long it would take for someone to produce antibodies because of repeat Roctavian infusions, for that we’ll just have to wait and see.
So, what next? Well, Roctavian has just been recommended for approval by the European Medicines Agency so it may become available in the EU very soon. I suspect the UK will follow as well, especially given the public disgrace the Infected Blood Inquiry is uncovering. The US are being a little more cautious in that they are waiting until the 7-year safety study has finished, but I suspect they will move pretty fast after that as it is the first time we have had a good and safe treatment for this horrible condition.
And here’s some more food for thought… we’re only just starting with this technology with haemophilia… this technology could be used for ANY single gene defect where an AAV is used to insert a correct gene into a cell… research is ongoing for retinal diseases, Alpha-1-antitrypsin deficiency, muscular dystrophies, Parkinson’s disease, Batten disease, cystic fibrosis, Alzheimer’s, spinal muscular atrophy, etc, etc… just imagine the potential benefits! Isn’t microbiology great? :-)
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