Valder R. Arruda, MD, PhD
Valder R. Arruda, MD, PhD, is a researcher in the division of hematology at The Children's Hospital of Philadelphia and an associate professor of pediatrics at Perelman School of Medicine at the University of Pennsylvania. He spoke with Healio about how gene therapy has impacted the field of hemophilia and what challenges still exist with this treatment option.
When I first came to Children’s Hospital of Philadelphia and the University of Pennsylvania in December 1997, there were several different groups that worked in gene therapy back then. Six months after I joined the team, I learned that there were experimental models in animals that were likely going to lead to the very first in-human gene therapy using an adeno-associated virus (AAV) vector. As a clinician, there were only limited options in treating patients with hemophilia, so I was interested to see this new option move from the bench to the bedside.
I view my career in gene therapy as developing in real time. There were two things I learned throughout my career. First, if a researcher wants to translate successful preclinical data, they are going to find obstacles. If they want to have a proof of principal in humans that is not only safe, but efficacious, they cannot just go around that obstacle.
There were several trials in the late ‘90s and early 2000s that mostly involved hemophilia A. These were first-in-human gene therapy trials, and some of them showed transient expression of 1% to 2%. Unfortunately, not many of them demonstrated long-term expression. Although some did show other developments, the focus started to revolve around AAV vectors for hemophilia B. The safety profile was extremely favorable, and we knew from previous animal models that we could achieve therapeutic levels in the muscle and maybe change the disease phenotype.
There were three different vector doses for three different patient cohorts that were initiated to help understand if it was safe, which proved to be true. However, the FDA along with other regulatory agencies and scientific societies released a statement in late 1998 that said that gene therapy had to be somatic and could not contaminate any germ cells. All of these trials were ready to begin, but the FDA stepped in and said that researchers needed to produce provocative studies to define which vectors were not able to transfer to the germline. We carried out experiments in rabbits and showed that intramuscular injection of AAV was not associated with the risk of germ line transmission.
There was an excellent safety profile, but a relatively low efficacy paved the way for the next AAV-liver directed gene therapy.
After a few months, a liver trial our research team was working on was given the greenlight by the FDA and we continued enrollment of patients. We followed these patients and identified that they had a transient detection in their semen that disappeared, as was previously proven in the rabbit model following intravascular deliver to the vector. When we went to the high-dose cohort, that was when we had the very first clear evidence that AAV was able to transduce the liver efficiently in these patients. We also recognized a cellular immune response triggered by the vector capsid, that was vector-dose dependent. The trails that followed were designed to intervene with a short course of immunosuppression that prevented complete loss of transgene expression.
In the future, I think we’re going to learn the best approaches with gene therapy and that more than one approach might be effective for hemophilia A and B.
We are going beyond phase 3 as a society, especially with what occurred in the last hemophilia workshop hosted by the National Hemophilia Foundation. There was a peer discussion on how much information should be shared. There was talk that companies could share information they collect, but still hold on to their proprietary interests, but allow researchers to learn from the biology.
It’s not that the FDA, in my opinion, is lowering the bar. The FDA is focusing on what is and what is not critical in terms of concerns. During the initial phases of a trial, there are many unknowns in the beginning, and you should consider everything to be potentially serious.
Over the years, researchers have identified what is and isn’t a problem. So, I think the less arduous review is because of the cumulative evidence toward several things that might not have implications, and therefore I think this is good to move ahead. Hemophilia is a good model because the outcomes are very uniform and very simple. Let’s use Luxturna (voretigene neparvovec, Spark Therapeutics), which was the first licensed gene therapy for blindness, as an example. The assessment of the phenotype, because it is a degenerative disease, is that if each eye were compared in the same patient, they may be different. That’s why with hemophilia it is easier because efficacy and safety are more straightforward. I think it is a positive thing that the FDA looked at that.
With the FDA commissioning a less arduous review for hemophilia-related therapies, we may be able to expand the options and some people may be able to go on to prophylaxis using gene therapy. An important thing that needs to be remembered is that the CDC estimates that 30% to 40% of young adults with hemophilia are not on prophylaxis.
Prophylaxis will help prevent a patient to not have spontaneous bleeding. But if a young patient plays football or soccer, that’s a different story. I think this will give them more options that can be simplified and possibly reach the goal of having a normal life – which means being exposed to minor trauma and not having to worry as much about spontaneous bleeds.
There is not a very good and efficient way to overcome the presence of high preexisting antibodies against AAV, which would allow us to do intravascular delivery. This is not only for hemophilia but is a limitation for all AAV treatments that are injected intravascularly. There are several attempts to do this through immunosuppression, but they are overall suboptimal. I think balancing a strategy that would be able to transduce all patients across a variety of AAV serotypes, will be important and have significant implications because it might work for other drugs.
Secondly, which is not yet a problem for hemophilia, is the need for vector readministration. For instance, how long will the expression of the AAV vector last?
The risk of AAV-capsid mediated immune responses can be overcome in most studies by transient immunosuppression and lowering the therapeutic doses of the vector is a very efficient to prevent this complication.
I think this was a brilliant idea. This was a small but very heterogenic group of individuals who were looking at hemophilia from completely different angles and is a very important step.
I’m excited about these results, but there are still a lot of open questions as to which outcome will be the most reliable. Most of the patients were not in prophylaxis. So it seemed like the reduced bleeding rate was straightforward, but there is more to this.
For instance, there are some disease complications that can be prevented most of the time. In hemophilia, it would be joint diseases. But that is a chronic process, so once it starts it is hard to stop. The question becomes, can a patient revert or not?
Some of these patients, especially older adults, may ruin their joints and then ultimately not have ideal treatments. That would be something that would require medical solutions, which maybe will help us learn that we can stop the progression of hemophilic arthropathy.
The thing that gets more complicated is, how are we going to charge for this? Should billing be based on duration or whether the patient achieves an ideal factor level? Should billing be based on how much vector is going to be dispensed, or should the specific vector that is going to be used be taken into consideration?
The outcomes will help us to refine answers to these questions and see which one will be a uniformed decision that will allow us to speak the so-called second language.
Arruda VR, et al. Blood. 2017;doi:10.1182/blood-2017-08-742312.
Iorio A, et al. Haemophilia. 2018;doi:10.1111/hae.13504.
Disclosure: Arruda reports no relevant financial disclosures.
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