Gene Therapy: New Technology

The onward march of science and haemophilia continue unabated. At the recent National Hemophilia Foundation Gene Transfer and Novel Technologies Workshop, there was over 30 presentations on current and future trends and developments in gene therapy, new approaches to extended half-life factors and other products for haemophilia. In the July edition of the magazine, I gave an update on gene therapy and on other new products including Emicizumab and Fitusiran. I also reported some preliminary results from some of the gene therapy trials. At that time we reported preliminary results on the Factor IX gene therapy trial carried out by Spark in the USA. This was the trial for which some people with haemophilia in Ireland had blood tests taken approximately two years ago. The latest data on that trial now shows that there have been seven patients infused with the gene therapy vector. It takes approximately 12 weeks for the Factor IX expression to reach a steady state. Of the seven patients infused to date, results have been reported on four who have been treated more than 12 weeks ago. Those four individuals who have been treated between 15 – 34 weeks prior to reporting have an expression level of 34% / 35% / 22% and 36% respectively. Results from the last three subjects to have been infused were reported a 2 to 8 weeks post infusion and their levels at the time of reporting were 25% / 11% and 16% respectively. These are very encouraging results. An update was also given on the Uniqure Factor IX gene therapy trial. They reported that 10 individuals have been treated to date. Those treated with the low dose achieved between 3% and 6.7% Factor IX expression. The results for those treated with the higher dose have not yet been reported.

University College London reported the updated results of their Factor IX gene therapy trial where they have dosed ten people with haemophilia with the initial vector achieving Factor IX levels of 3 – 4%. They plan to use a new vector together with the Padua Mutation which expresses Factor IX at a higher level in their new Factor IX trial. A Factor IX trial carried out by Dimension in the USA has been halted as the results were not consistent (one person with haemophilia who was infused with this vector is expressing a level of Factor IX between 20 – 25% but other individuals have lost any Factor IX expression which they had initially gained without any obvious explanation). Updated reports were also provided on the Biomarin Factor VIII gene therapy clinical trial. They have treated nine patients to date.The individual treated at the low dose did not achieve any significant rise in expression, the individual treated at the medium dose achieved an expression of 2% and seven individuals were treated at the higher dose.  Of these seven, 1 achieved an expression of 10% and 6 achieved an expression of more than 50% with 2 of the 6 now reporting levels in excess of 200%. While these levels in the last two patients are certainly higher than you would expect or hope to see, it is clear proof that Factor VIII gene therapy should work. Work in ongoing in all of these trials and we anticipate people in Ireland with haemophilia having an opportunity to participate in some of these gene therapy clinical trials in 2017 and 2018.

The companies are working to continuously improve their gene therapy delivery systems, to decrease the risk of an immune response to the gene therapy vector and to use new variants of the Factor VIII or Factor IX gene,  which will provide higher expression without necessarily having to give a higher dose of the vector. The vector delivery system used for the current gene therapy trials are Adeno-associated virus (AAV) vectors. These AAV vectors enter the liver cells and cause the liver cells to start producing the Factor VIII or Factor IX respectively. They are not however integrated into an individual’s DNA. A separate type of vector called a lentiviral viral vector is also being looked at for future clinical trials. This vector would be integrated into the DNA and it was stated that these type of vectors may be an option for future gene therapy in children. The current vectors are not ideal for children as in growing children the liver cells turn over more rapidly and therefore the expression gained through the gene therapy could be lost. Another advantage of these type of vectors is of course that they would not exclude the approximately 40% of people who have existing antibodies to the AAV vectors which means they cannot be treated with gene therapy using a specific AAV vector. The conference also discussed future funding for gene therapy. This is going to be a challenge. The two gene therapies for other conditions which have currently been launched on the market are priced at $1 million and €650,000 respectively. Governments and paying authorities will want certainty in terms of budgets. In my view, for countries with a national healthcare system including Ireland, the UK, Canada and Australia and many European countries, the most likely future model for making gene therapy available would be an amortisation system where the cost of gene therapy would be spread over several years and the payment of that fee over several years would be contingent on continued expression of the Factor VIII Factor IX level. This will be an interesting economic and scientific area and we will watch developments carefully.

In addition to gene therapy, advances are being made in relation to gene editing. There are now techniques under development which can be used to cut DNA sequences of an individual at specific points and to add, change or delete specific gene sequences in the gene and therefore apparently modify the person’s genetic code. These techniques which were referred to as “molecular scissors” could be used within the body or cells could be manipulated outside of the body and then re-inserted. There are promising technologies which now look as if it may be possible to edit, insert or delete specific parts of the gene to deal with Factor VIII or Factor IX deficiency.

There are now three Extended Half-Life (EHL) concentrates licensed in Europe, comprising of one Factor VIII EHL product and two Factor IX EHL products. The EHL Factor VIII product (Elocta) is already being used for treatment in Ireland by a number of children and adults. There are further EHL FVIII and FIX products coming down the pipeline which should be available and licensed in the next year. However, development of EHL factors will not stop there. At the conference, there were a number of significant updates in relation to potential future developments. One company is developing a FVIII product which will double the FVIII half-life to 24 hours. Probably the most significant barrier to increasing the half-life of EHL of FVIII is the fact that when FVIII enters the body, it couples with von Willebrand Factor (VWF) and this limits the half-life. One company is fusing an EHL FVIII product to a protein sequence which is derived from a specific region of the VWF. This product when infused, will not couple with the VWF and therefore this would remove the limiting factor to increasing the half-life. They anticipate increasing the half-life from the current EHL  FVIII of 15-19  hours up to 39 hours allowing for once per week FVIII prophylaxis. EHL FIX when fused to this protein sequence will potentially increase the half-life to the extent that it would allow for FIX prophylaxis once a week subcutaneously rather than intravenously.

The conference also heard about a number of significant developments and research in relation to inhibitor treatment. There is a version of the Recombinant Factor VIIa product being developed which will increase the half-life from 1.7 hours to 5.1, a 3 fold increase. Other groups are working on antigen-specific immune therapies which may neutralise inhibitors. One very unusual approach was taken by an American company who have been attempting to orally induce tolerance for haemophilia B inhibitors using lettuce. They encapsulate the FIX gene in lettuce cells. In this format, it is protected from acids and enzymes in the stomach and it can be delivered orally. When this product was given to dogs with haemophilia B it succeeded in tolerising some of the dogs (3/4 dogs were tolerised). In these dogs following the ingestion of this lettuce containing the FIX gene, these dogs when exposed to human FIX concentrates did not develop inhibitors. Control dogs who were exposed to FIX without the ingestion of lettuce prior to exposure did develop high titre FIX inhibitors. This is a novel concept for oral tolerance. It would be more difficult to do this for FVIII, as the large size of the FVIII protein makes this harder. Interestingly the dogs were encouraged to eat the lettuce by engineering bacon flavoured lettuce. It is highly unlikely that all of these developments will succeed but it is very likely that many of them will succeed and I am confident that the therapeutic landscape for haemophilia will be completely transformed in the next 5 – 10 years.

Brian O\’Mahony,
Chief Executive.
December 2016