My gene therapy journey  

Mr Brian O’Mahony, Chief Executive, Irish Haemophilia Society, recounts his experience of participating in a gene therapy trial for the treatment of his haemophilia

I was treated with factor IX (FIX) gene therapy as part of a phase 3 clinical trial in February 2020, some 57 months ago. At the time of treatment, I was 62 years old and had lived a life encompassing all of the generations of haemophilia treatment.

Until I was age 14, I had no access to any regular treatment and bleeding episodes went untreated. As a consequence I had damage to my left knee, right ankle, and right elbow. At age 14 I had my first treatment with a factor concentrate which was actually a prothrombin complex concentrate containing a mixture of factor II (FII), factor VII (FVII), FIX and factor X (FX). For the next three years, if I required treatment, it was fresh frozen plasma which necessitated a 400 mile round trip from Killarney to the treatment centre in Dublin. Obviously given the time it took to get to Dublin, a bleeding episode in a joint would be well advanced by the time that the plasma was infused.

When I moved to Dublin to go to college at age 17 I had access to home treatment with prothrombin complex concentrate. This was the treatment available until my early 30s when I switched to plasma derived FIX concentrate. Then in my early 40s, recombinant FIX became available, and this was my treatment of choice until my late 50s when I switched to extended half-life FIX concentrate. I did not start prophylactic treatment until my mid-50s.

Of all of these treatment changes, in my view, the availability of home treatment where you could treat a bleed quickly, as soon as it had started, was the single biggest game-changer. The availability of extended half-life FIX was also a significant milestone which allowed me to take prophylaxis once every 10 days while maintaining a trough that kept me in the mild range.

A carefully considered decision

My decision to take part in a gene therapy clinical trial was a carefully considered one. I had been following the science for many years. Together with our clinicians, I had been involved in encouraging several of the companies who were conducting gene therapy clinical trials to consider Ireland as one of their venues for the trials. Over the course of the past 10 years, we had several companies who came to Ireland to discuss their gene therapy clinical trials with the clinicians and patients. I organised group meetings for the Society, usually for 10-to-20 people with haemophilia who had expressed some level of interest in gene therapy, to come along and hear more about the trials. We also worked with the Irish regulator to make sure that the trials could take place in Ireland. During the course of these meetings and following my reading and research into gene therapy, I became convinced that the benefit-risk ratio for me personally of participating in a gene therapy clinical trial was positive. I was convinced by the science of the potential of the gene therapy.

Before enrolling I was aware of the unknowns and uncertainties. I knew that there was no guarantee of durability. I knew there was no guarantee of achieving a particular factor expression. I was aware some people may not get a response to gene therapy and would not achieve any significant factor expression. I was aware of the potential requirement to take steroids in the event of transaminitis in order to prevent any potential loss of factor expression achieved. I was aware of the theoretical risk of cancer from insertional mutagenesis because of some integration of the infused DNA into my own DNA.

Despite these uncertainties, I felt that participating in a gene therapy clinical trial was the correct decision for me. I discussed this with friends and colleagues – both clinical and haemophilia organisation leaders who had a range of opinions in relation to gene therapy. I discussed this with my family, but they were very clear that they trusted my judgement and knowledge. Within the parameters of the uncertainties in durability, factor expression and predictability, I identified for myself my preferred personal outcomes while at all times being aware that these may not be achieved. If these were not achieved I believed I was ready to accept whatever outcome I did achieve.

My hopes

I was hoping for a factor expression in the range of 20-to-60 per cent. My preference was for my factor expression not to be too high as I wanted to maintain some of the potential cardioprotective effect of a slightly lower factor level given my age. I hoped for a durability of at least 10 years. I hoped for a decrease in chronic pain in my damaged joints and for the ability to be more physically active and physically fit.

Obviously if I achieved a significant FIX level, it would mean I could stop prophylaxis. This in turn would free up some of my time and allow me to have some mental freedom from dealing with my own haemophilia. I was fully aware that given my roles with the Irish Haemophilia Society, European Haemophilia Consortium, and ongoing work with the World Federation of Haemophilia, I would not and could not achieve anything like a ‘haemophilia-free mind’, as my entire working life is consumed with haemophilia and bleeding disorders. I did hope for some freedom from dealing regularly with my own haemophilia, including in areas such as not having to take prophylaxis on the days of long-haul flights and carefully planning any significant physical activities to coincide with prophylaxis days.

There were other factors in my decision also. At my age of 62, if it took several years for gene therapy to be licenced and reimbursed in Ireland, I may have missed my opportunity to receive it. I have lived my entire life with severe haemophilia – I thought it would be interesting to try life possibly without severe haemophilia. I also wanted to lead. Despite the meetings over several years, no person with haemophilia in Ireland had participated in a gene therapy clinical trial. I was the first and I was quickly followed by two others.

The preparation and process

With the decision made I entered into a lead-in period of approximately six months before the gene therapy was infused. During that time period I had to keep an electronic diary recording and including any bleeding episodes and prophylaxis. I also engaged extensively with the research team at the centre where the gene therapy would be infused. In the year prior to my gene therapy in 2019, I had travelled abroad frequently to conferences and to deliver lectures and I travel extensively for work.

I had several conversations with the research team in relation to ensuring that we could schedule my follow-up appointments ideally allowing me to maintain some of my work commitments abroad. Having said that, I was fully aware of the monitoring and follow-up requirements and fully committed to the protocol. I wanted the gene therapy to be successful and I did not want to jeopardise the potential for success or jeopardise the trial protocol because of travel commitments. The monitoring visits required a visit once-weekly for the first 12 weeks, followed by monthly visits for the rest of year one and bi-annual visits after that up to the end of year five. I was fully committed to making all of these visits and willing not to travel if that would interfere with my ability to stick to the protocol.

Ironically, that was not necessary as two weeks after my dosing, the Covid-19 pandemic struck and I had no travel commitments for at least the next 18 months. This made it easier to manage my diary and schedule all the monitoring visits while simultaneously making it more difficult, as it meant I had to attend a hospital setting very regularly during a pandemic at a time when most people did everything possible to avoid going into any hospital. The research team made this easier by facilitating the visits in a non-clinical setting where potential exposure to Covid-19 was very limited.

The gene therapy infusion day was relatively simple and uneventful. I attended at the research facility near my haemophilia treatment centre with my wife about two hours prior to the infusion to have some blood tests, final checks, and final conversations. I received the infusion over about a 90-minute period, waited two hours, and went home. The procedure was simple although I was aware that they had an emergency team ready if required in case of an adverse reaction. I was very relaxed during the day, but that evening I was emotionally drained as I realised what a momentous day this had been for me.

I then had weekly visits for the first 12 weeks and indeed I exceeded this for several weeks by having twice-weekly visits. I wanted to make absolutely sure that there was no possibility they would miss any increase in liver enzymes which could result in loss of expression if there was a delay in diagnosing this and in commencing steroids. The visits were very well managed in a non-clinical space due to the pandemic. The only adverse event I had was a decrease in my iron due to the sheer volume of bloods being taken on a weekly basis.

In the first year I had twice-weekly visits for the first three months and then monthly visits. In total in year one, I visited the centre 30 times. I adhered fully to the protocol and abstained from alcohol for three months pre gene therapy and two years post gene therapy (exceeding the one year recommended.)

My outcomes

My outcomes from day one were good. My FIX level increased from week one and has stayed in the high mild or normal range over the past 57 months. Thankfully I did not require steroids as my liver enzymes never increased. I did have some decrease in chronic pain in some of my damaged joints, partly I suspect due to gene therapy and partly due to additional time since my knee replacement in 2018. I was fitter and more active in the first year post gene therapy due to the therapy itself and the fact that I was not constantly travelling and was able to get into a balanced regime of exercise and diet.

On the first anniversary of my gene therapy I was walking with my family in the Dublin mountains when I slipped and fell off a low wall onto some rocks. Despite this I did not get a bleed and this was a revelation to me. On another occasion in the first year I dropped a 2kg dumbbell on my barefoot and again did not get a bleed. I have had two bleeding episodes since commencing the gene therapy, one which was spontaneous and one which was due to a trauma. I have also required FIX on a couple of occasions to top-up my factor level prior to a minor surgery or procedure.

Now that we’re in a post Covid-19 environment I am travelling again for work. I generally do not bring any FIX with me unless it is a long trip or a trip to a developing or emerging country where I would have difficulty accessing treatment if required. For exercise I walk routinely. I commenced using alcohol moderately two years after my gene therapy infusion. I had a brain lesion last December which required lengthy surgery. Thankfully, the lesion was benign. It was checked to see if it was in any way related to my having had gene therapy. While the final results are not yet available, preliminary findings and the type of lesion were both strong indications that it was not linked to gene therapy and may in fact have been growing slowly for several years. I am now also dealing with some other minor health issues not related to haemophilia. I continue to follow the science around gene therapy very closely and I have to say that personally I have no treatment remorse. I made the correct decision for me at the time. My outcome has been good, but I would like to think that even if it had been less satisfactory, I would not have treatment remorse because I had fully thought through all the outcomes that may occur and I had managed my expectations accordingly. The key is to make a fully informed decision based on information, discussion, and careful consideration of all the potential benefits and risks with input from the clinical team, family, and also from the Society.