Steven Pipe, MD: What we've highlighted so far are the benefits of prophylaxis by replacing factor 9 [therapy] with an IV infusion. However, the limitation of that is the need for an IV to deliver that and then the limitations of maintaining sufficient levels so you don't have breakthrough bleeding. The promise of gene therapy is to achieve a steady state, a measurable level of factor that's above key thresholds that would also produce a steady state hemostatic effect sufficient to prevent bleedsall of this following a single treatment intervention. How do we achieve that? The first wave of gene therapies for hemophilia are adenocarcinoma-associated virus-based liver-directed approaches. What we do is a functional copy of factor 9 [therapy] is packaged inside a viral vector, these AV vectors, and the vector contains no propagating viral gene elements. Following a single outpatient IV infusion over as little as 13 hours, these viral particles that contain the factor 9 gene are picked up by the liver cell receptors, and they're taken into the cell. The vector particle uncoats, and it delivers the DNA to the nucleus of the cell. The genetic elements that accompany the gene allow for efficient expression and then secretion of factor 9 protein into the plasma. This reaches a steady state between the rate of secretion from the cell, as well as the clearance from the plasma. That's represented by a factor level that we can measure with traditional blood sampling. If we get those patients up to a sufficient level, they can come off prophylaxis. They may not need factor episodic doses related to trauma if they're at a high enough level, and we can allow them to leave. Hopefully, [this will] allow them to live the life that they choose related to their activity levels, the occupations they want to be involved in, and bring a lot of spontaneity back to their life.

Hemophilia A and hemophilia B gene therapy are similar in concept. However, there are some challenges related to hemophilia A, in particularly factor 8 expression using this strategy, that might make this easier for hemophilia B to come to the forefront of clinical care delivery. One of the biggest differences is the size of the gene itself. The factor 9 gene is considerably smaller than the factor 8 gene that's used for hemophilia A. In fact, the intact factor 8 gene is far too big to fit inside these AV vectors. We use a modified trans-gene in order to package it inside the vectors. In addition, factor 8 has some challenges related to how efficiently the cell can make factor 8. The other aspect, which is interesting from a biological perspective, is that factor 9 is naturally made in the hepatocyte of the cell. However, factor 8 is not primarily made in the hepatocyte; it's made in a number of different tissues in the body, primarily endothelial cells. Trying to express factor 8 within that hepatocyte, which, if you like a non-native cell, has become considerably more challenging. What has this meant in the observations from the trials? We've been getting more consistent and durable expression of factor 9 in the hemophilia B trials than we've seen in hemophilia A. Seeing this get approved at the regulatory level, and then also approved for reimbursement at the payer level, I [now] have a higher level of confidence that hemophilia B might achieve that earlier. We'll be able to incorporate that into our clinical care delivery earlier.

If gene therapy is actually able to come to the forefront as part of a clinical care delivery, this [will] be a game changer, at least for a proportion of the patients we have in our clinicsto be relieved from the need for regular prophylactic therapy, including the burden of the commitment, the need for IV infusions, the economic burden associated with the prophylaxis. You no longer have to worry about doing prophylaxis or even having breakthrough bleeding [from a single treatment event]. You can carry your life forward, not having to think about your hemophilia. These are all significant advantages of this treatment. There's going to be several patients who want to have that kind of transformation and live the life that they choose. We're going to see some limitations in that approach because this is going to be applied according to the eligibility and restrictions associated with clinical trials. Out of the gate, this will be a smaller proportion of patients who are going to benefit from this, a truly transformational treatment.

Transcript edited for clarity.

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Defining the Impact of Gene Therapy - Managed Healthcare Executive