Steven W. Pipe, MD, is an associate professor of coagulation and director of the special coagulation laboratory at the University of Michigan. He spoke with Healio about how recombinant DNA has impacted the field of hemophilia and what future research should entail.
Steven W. Pipe, MD
When I started in the clinic in the early 1990s in the United States, we were beginning the major shift from on demand treatment for bleeding in hemophilia to prophylaxis. When product was limited, particularly when it had to be extracted from plasma derivatives, the most widely used solution was to wait until a bleeding event occurred and have the product available at home for the families to infuse as quickly as possible. But that solution really did not address the fundamental problem of hemophilia, which is the prevention of bleeding, the primary manifestation of the disease. Prophylaxis was piloted in the Swedish population and showed effectiveness in preventing joint disease. While we were making the shift in the United States, a definitive randomized, controlled trial conducted in the United States called the US Joint Outcome Study, definitively compared aggressive on demand treatment to prophylaxis. The study conclusively showed that not only could bleeding be prevented with prophylaxis, but in doing so boys’ joints could be preserved for many, many years. We very quickly adopted prophylaxis as a standard of care for hemophilia. The other major transition was from plasma derivatives to recombinants. The genes for recombinant factor IX were cloned in the mid-1980s but we had recombinant replacement proteins available for treatment right around 1992. Again, right as we transitioned into the clinics, we began the major transition away from plasma derivatives to recombinant factor VIII.
Prophylaxis was initially pushed to the pediatric age group and adolescents. However, having just a few joint bleeds early in life can do enough damage in the joints to cause arthropathy later so in our clinics we place a great deal of effort into finding ways to introduce prophylaxis as early as is practically feasible. Now we start prophylaxis around 7-to- 9 months of age as soon as venous access can be achieved practically. Then we trained the families to continue that prophylaxis in the home setting. We’ve also expanded prophylaxis to adults who were never on prophylaxis. That’s considered tertiary prophylaxis and has shown good results in keeping older individuals with hemophilia from having breakthrough bleeding that would cause them to miss time from work. Tertiary prophylaxis also reduces joint pain and preserves joint function for a lot of older individuals. Those are some of the practical changes that we’ve seen.
The availability of products has also changed drastically in the last several decades. The recombinant DNA technology platform opened all kinds of innovation. We’ve had a wave of extended half-life factor products, for both factor VIII and factor IX, which have not only expanded the armamentarium of available products but have different mechanisms of action. Better availability has given us the opportunity to select the products that work best for individual patients, reduced the burden of the frequency of prophylaxis for many patients, and allowed us to achieve better joint outcomes in other individuals who are still struggling with breakthrough bleeding on standard half-life products. With this expansion of new products, the availability of products for the developing world increased. Something that has impressed me over the last 20 years are the optimal outcomes we have been able to achieve in the developed world; the developing world has sorely lacked access to products. There is no real availability for prophylaxis in a lot of countries. About 75% of the world has inadequate treatment for hemophilia, but I have some confidence that with these expanded products, more and more product is finding its way to the developing world and that’s going to improve outcome for patients across the world as well.
With plasma-direct products, you are stuck with the natural form of the protein. There’s obviously some benefits related to the natural form, but the recombinant DNA platform allows essentially unlimited opportunities for innovations to the molecule. What we’ve seen in recent years is modifications to the DNA sequence to improve the property of the protein. We’ve seen the use of conjugates through pegylation and fusion proteins, both fusion to the SD fragment of anticoagulant as well as to albumin. This allows for reduced clearance in plasma and extending the half-life of those molecules. Similar innovation might lead us towards molecules that are potentially less immunogenic, and maybe allow for alternative modes of delivery.
At the extreme end of innovation on the recombinant DNA platform is the newest therapy, which is not replacement therapy but a substitution therapy in the development of emicizumab. Emicizumab is humanized by a specific antibody that recognizes factor IXa and factor X and mimics or substitutes for the cofactor function of activated factor VIII. The new therapy has had a major impact on the care of individuals with inhibitors to factor VIII, since it doesn’t cross-react with antifactory antibodies. Emicizumab was approved just last year and is increasingly being used in this population of patients. In the last month, we’ve seen the data from clinical trials of emicizumab in non-inhibitor patients with hemophilia A. In a comparison with the historical treatment in those individuals on routine factor VIII prophylaxis, emicizumab had superior bleed control. That product is on an accelerated pathway with FDA for review and I think it’s entirely possible that emicizumab may have an extended label sometime later this year. The recombinant DNA platform is opening these kinds of novel therapies for patients.
There are several aspects that are unique to the emicizumab platform as a therapy. It has been presented as a paradigm shift in how we think about hemostatic therapy for hemophilia. Relatively rapid clearance after infusion challenges traditional protein replacement. In traditional protein replacement, you get peaks and troughs with the infusion. Practically, patients are reinfused at trough levels where their residual factor levels are quite low – maybe close to 1 to 2% – and during the window leading up to that next dose, they are at risk for bleeding. The extended half-life molecules have either improved the convenience of dosing by allowing for stretched out intervals, or they’ve allowed us to maintain trough levels that are higher to reduce the risk of bleeding and improve joint outcomes.
But substitution therapy with the very long half-life, like emicizumab, allows us to achieve steady state levels with longer dosing intervals, up to 1 month from the most recent clinical trial reported. This essentially eliminates the peaks and troughs that are familiar to replacement therapy and so we have a steady state level that has never really achieved outside of gene therapy. The level of protection achieved remains a challenge. We don’t think emicizumab levels we’re using in the clinical trials and commercially are the equivalent to normal factor VIII correction. Nevertheless, the results from the studies would suggest emicizumab maintained a level of control that for the majority of people eliminated spontaneous joint bleeds. They may still be at risk for traumatic breakthrough bleeding but have experienced a type of hemostatic protection with this new steady state level.
The subcutaneous dosing is also a significant breakthrough. We’ve been able to get by with intravenous access in patients with hemophilia for some time, but some patients, have to use central venous vein access devices, particularly young children. Prophylaxis is not often used in the first year of life because of the practical challenges of doing regular infusions intravenously in small infants. Older individuals could have challenges with venous access as well. Perhaps emicizumab can open prophylaxis to much earlier and later age groups. You have the convenience of the very long dosing intervals, the subcutaneous administration and then the steady state levels that can be achieved.
That’s been more challenging. In the early days when factor products essentially had the same efficacy and similar mechanisms of action, there wasn’t much reason to switch between products to evaluate their efficacy because they all behaved very similarly. It was more about what level was achieved in that patient, and the interindividual variability was there. Particularly with the factor VIII products, some patients have a half-life as short as 6 to 8 hours. Other individuals can have a considerably longer half-life up to 16 to 20 hours. Efficacy wasn’t a product-specific phenomenon; efficacy was related to patient’s individual clearance rate. We haven’t unlocked what genes regulate the half-life in individuals. Now in the era of next-generation sequencing, we might be able to get some insights on the genes that regulate factor VIII clearance. But with new molecules have new different mechanisms of action, including pegylation, Fc fusion, and albumin fusion. Having different mechanisms of action has provided the opportunity to see if certain molecules behave better in certain individuals. I wouldn’t say there’s a specific test that can help define that, but through empirically trying these products in patients, we can try to find the product that provides the optimal outcome for that individual.
Better understanding and recognition of the individual pharmacokinetics for individual patients can help us find the optimal product. A traditional pharmacokinetic analysis is a dozen or so blood draws after an infusion, but with the use of population pharmacokinetics on a couple of samples after a dose of a factor and comparing against a database that includes population pharmacokinetic data, we can get a good estimate of a agent’s half-life for a specific patient with fair accuracy. There’s at least one commercial tool for one product that allows doctors to take advantage of these population PK based on the database on that product. I think that the renewed focus on individual pharmacokinetics is just another refinement of treatment, so we can match the mechanism of action of a drug with the most optimal outcome for a patient.
We still have challenges that the recombinant platform hasn’t fully addressed. Most products outside of emicizumab are still given intravenously. If there were a way to make some of the other traditional agents bioavailable through subcutaneous mechanism, that could potentially be an advantage. The cost challenge is a difficult one as well. Hemophilia prophylaxis costs anywhere between $250,000 and $400,000 per year. Some innovations to bring down the cost of therapy would be welcomed. We have not significantly researched the risk of inhibitor formation, particularly in hemophilia A. As far as we know, a patient with severe hemophilia A probably has a risk approaching 30 to 40% of developing an inhibitor antibody response with their initial exposures to factor VIII. This poses a range of challenges for the patient. Both the inabilities of factor VIII and the need to use bypassing agents for bleeding that are not as effective as factor VIII replacement make prophylaxis more challenging. Some innovations to possibly either deimmunize factor VIII or to partner it with technologies that would reduce the risk of inhibitor formation are interesting areas of focus. Additional research into understanding what genes regulate individual pharmacokinetics is needed as well.
Those are all good areas of focus, but where the field is really shifting is toward definitive replacement therapy, which would ultimately come from gene therapy. Instead of making recombinant proteins in the main factoring facility, we move the recombinant DNA into the tissue of the patient, so they make the protein themselves. That’s the underlying principal of gene therapy and hemophilia. Worldwide, there’s multiple ongoing trials with significant successes. In some cases, at the highest doses of these trials, patients have achieved curative levels of factor VIII and factor IX. With the current approach of using adenoid-associated virus, the safety profile looks encouraging and the durability looks strong. These patients achieved steady-state correction of their factor VIII and factor IX levels and they probably will hold on to that expression for a decade.
As for recombinant DNA, there’s been wonderful partnering between the vector technology and bioengineered forms of factor VIII. The two most successful general approaches for hemophilia B and hemophilia A both involve bioengineered molecules. For hemophilia B, all of the programs have moved toward using a hyper-active form of factor IX. This is a point mutation that is introduced into factor IX. Essentially all of the factor VIII gene therapies use a bioengineered form of factor VIII that truncates the size molecule to facilitate better packaging. In some cases, researchers introduced additional modifications to improve the expression efficiency, like coding optimization and introducing targeted glycans to improve the secretion efficiency. Partnering between bioengineering, recombinant DNA technology and gene therapy is what’s really taking us to the next level for outcomes for patients.
Please click on Next tab to advance through activity.