A Novel Way to Deliver Rare Disease Therapies

One of the challenges of delivering enzyme replacement and other therapies to treat rare diseases is the questions of how to best deliver them. EryDel is developing therapies that can be encapsultated in a patient’s red blood cells through its proprietary, point-of-care device. We spoke to Luca Benatti, CEO of EryDel, about the company’s technology for encapsulating medicines in red blood cells, its pipeline of rare disease therapies, and the advantages delivering treatments this way.

Daniel Levine: Luca. Thanks for joining us.

Luca Benatti: My pleasure.

Daniel Levine: We’re going to talk about EryDel, its drug delivery technology for encapsulating therapies in patients’ red blood cells, and why this can have particular benefit to patients with rare diseases. Let’s start with the why. Why deliver medicines by encapsulating them in red blood cells?

Luca Benatti: Yeah, the technology we are using, which is coming from decades of work on the red blood cells by our founder, Professor Magnani, took the advantage of the feature of these cells: that they are cells without genetic material, so without nucleotides; and the second aspect of these cells is the fact that when they are exposed to different solutions, different hypertonic solutions, their membrane becomes loose to allow drugs to be incorporated into the cells and then received. And in this way, you can use this as a vector for your therapeutics and when the cells are reinfused back into the patients you have the advantage that they will reach any compartment in the body.

Daniel Levine: How does encapsulating therapeutic in a red blood cell affect things like its half-life and alter dosing regimens?

Luca Benatti: For instance, we have many different applications. The first one for our lead product for ataxia telangiectasia, this rare neurological condition, is a prodrug of the known steroid dexamethasone that if infused directly into the bloodstream as a half-life of a few hours. The way we have used the red cells with the slow release mechanism is to produce an infusion every month, and it releases therapeutic over the entire month—so prolongs the half-life from few hours to a month.

Daniel Levine: And is that something you can control?

Luca Benatti: Of course, you can control it with the quantity of the payload. You can control it with different procedures, but that is one only application of our technology. The second applications is not based on a sustained release formulation. It is based for our enzyme replacement therapies for other rare disease conditions on the fact that the enzyme does not require to be released from the red blood cells, the red blood cells in this case act as a shedding of the proteins from the immune system. So, they protect exposure of these recombinant proteins from the immune response of the body that is a significant limitation of the known therapeutics. As you can see, there are many different ways of applying and using the red blood cells as a means to improve half-life, but also to protect from immune system a different therapeutic. Also, in the case of enzymes, you have an advantage that instead of single daily infusions, you may deliver the infusions on a monthly basis. So, you also prolong their life.

Daniel Levine: There are a number of companies seeking to encapsulate medicines and platelets or white blood cells. Is there a particular advantage to the use of red blood cells or are there certain indications or types of therapies for which these cells would be well suited?

Luca Benatti: I think the capabilities of encapsulating drugs in red blood cells are much wider. We have demonstrated that we can go from very tiny, small chemicals to large proteins, RNA therapeutics as well as supermagnetic nanoparticles for imaging. So, the flexibility of the red blood cells is enormous. And on top of that, the transfusion data on erythrocytes and function of the erythrocytes and the biology beyond the erythrocytes provides a safety database that makes these cells, I believe, more flexible and suitable for approaches of this kind.

Daniel Levine: Erydel has a platform technology for point of care encapsulation of large and small molecule therapies. How does this work? Walk me through the process.

Luca Benatti: You’re right. We are unique because we have developed a device, which is a small machine that can perform fully automated the procedure of processing the blood of the patients, and when we say process the blood of the patients, we don’t mean processing the entire blood of the patients. We are talking about a syringe of blood, so 50 milliliter of blood, a very small amount. So that is processed by the machine automatically, which does all the steps that are required for cleaning the cells, opening the cells, infusing the drug, closing the cell, and having the final product ready to be infused back into the patients. This is done with this machine and a trained operator that is operating with the machine, but the machine is fully automated and controlled by a software. And that process require a couple of hours from the time you take the syringe of blood from the patient to the time the patients can go home with the drug inserted into the small sample of erythrocytes.

Daniel Levine: And can this technology be used with any existing therapy or do they require therapies to be specially formulated for the process?

Luca Benatti: So, if your question is related to the payload, we can add any kind of payload, but clearly the application of our technology is where there is an unmet medical need. So, is there an unmet medical need, for instance, in case of an ataxia, the fact that the oral medications available cannot be used in these patient populations because of the side effects, and you need to create the formulation that makes the drug available to the patients in a form that is not creating substantial side effects of chronic use. That is where our applications is for enzyme replacement therapies. As I said, the enzymes available now as therapeutics have enormous limitations and cannot be used in the majority of the patients. So with our shedding procedure with the red blood cells, we will make enzyme therapeutics available to a broader set of rare disease patients suffering from phenylketonuria, refractory gout, these kinds of diseases.

Daniel Levine: And who performs the encapsulation? Is this something done by people who are specially trained? Is a doctor or a nurse or a pharmacist likely to do this?

Luca Benatti: Yeah, the company has very strict rules and QA and QC procedures. What we do, when currently we are not commercializing any of our products, we have conducted up to a phase 3 development in in this rare condition. So, what we do, we install the machine with our personnel and we train the nurse that is handling the blood. The nurse, once he’s qualified and trained, he can perform the procedure and take the blood, process it with the machine, and infuse the blood into the patients. And only trained personnel are allowed to use the machine. But as I said, this is an almost fully automated machine. So, the level of training is fairly limited, but the qualification is a mandatory for using the machine.

Daniel Levine: As you’ve mentioned, your lead experimental therapy is a treatment for ataxia telangiectasia (AT). For listeners not familiar with AT what is it?

Luca Benatti: Yeah, unfortunately it’s a devastating disease. It’s a genetic disease and affects children in the early years. Children manifest a form of ataxia; they have problem with their coordination and movements primarily. And the problems developed up to a point where most of them in the second decade of life became wheelchair bound. They start having speech problems, communication problems, coordination problems, and their quality of life is, of course as you can imagine, dramatically affected. Unfortunately, in the third decade of life most of them die from the disease and its complications. So currently there is no treatment for those patients. We are the only company that has been able to move into a phase 3 trial with a potential therapeutic. And our phase 3 trial showed that there is a significant benefit to those patients suffering from the disease. So, the commitment the company has is to now negotiate and discuss with the regulatory agencies for taking this product to the market.

Daniel Levine: What is your lead experimental therapy Erydex and how does it work?

Luca Benatti: Yeah, the starting point for steroids in this disease and the benefits with steroids in this disease was a serendipitous finding based on an early discovery as has happened many times in medicine. There has been a great deal of effort by different investigators to try to use steroids in these patient populations. But as I said, this is a very fragile population of patients suffering from several immunocompromised conditions and therefore the usage of steroids causes significant side effects and problems. So, what Erydex as demonstrated in the phase 3 trial has been to show that those limitations of the oral steroids are overcome by the delivery system, that we can provide a reasonably safe chronic therapy to these patients. And more importantly, that we have shown that there is a benefit that delays the progression disease in the patients.

Daniel Levine: And what’s known about the safety of the therapy?

Luca Benatti: Yeah, so we have treated 175 patients in the phase 3 trial. The phase 3 was designed as a placebo control, 12 month trial with an extension in an open label phase. And we have patients now on the drug for more than two and a half years. So, the patients’ safety profile as compared to the placebo is excellent. We didn’t have the imbalance on the safety signal. And particularly with focusing on the typical steroid side effects, these were not of any concern by the safety monitoring board that reviewed the entire data set.

Daniel Levine: And what’s the approval path forward? Does this get treated as a conventional drug? Is it treated as a drug device combination?

Luca Benatti: Very good question. So, this is going to be a drug device combination, and actually the FDA in reviewing the request for designations is referring to this as a combination product. But ultimately since it is the drug providing the benefit, they appointed the CDER as the drug division of the FDA as the lead department for the review of the dossier, but everything is under the IND, but all the biologic aspects of our product, which are the red blood cells, as well as the medical device part of the product are included into the IND, but they are being taken care of by a combination of different expertise and divisions at the FDA.

Daniel Levine: You’re also looking at Erydex in other indications, including for Duchenne muscular dystrophy. Is there an expectation that you’ll look at it for broader potential uses beyond those you’re already pursuing?

Luca Benatti: Yeah, the suggestion we had by talking to experts in different fields, there was for instance, from the Duchenne point of view where there is an established usage of steroids, if we can come up with the set of data that shows the long term safety and clean safety profile of administration with Erydex, it would be very interesting to look at the opportunity also in the Duchenne muscular dystrophy, and this could be an area where we are going to invest as well as, as suggested by KOLs. Now that we have data in one form of ataxia, having those different attacks, some similarity in these symptoms, it would make sense probably for us to explore for the interest of patients suffering from other forms of ataxia, the benefit of Erydex in those other forms of ataxia. So, this will be the area of focus once we better clarify the regulatory pathway and the commercialization of our lead indication.

Daniel Levine: You also talked earlier about pursuing enzyme replacement therapies for such conditions as PKU. What’s the advantage to this delivery method for existing enzyme replacement therapies.

Luca Benatti: Yeah. For instance, if you take PKU and products that are currently on the market, like Palynziq, this is an enzyme that is injected directly. It’s a common enzyme from bacteria that is injected directly into patients. There is a black box warning because there is a significant risk of an anaphylactic shock, and you have to titrate the product, and in some cases up to six months to reach effective treatment. And you have a significant amount of antibodies generated that limit the benefit of the therapy. So, that is a significant impediment of usage of Palynziq that by the way, is also not prescribed for pediatric populations, which is the population with the highest unmet medical need, because it is where the neurological symptoms start to kick in when the patient becomes an adolescent. So, there is a huge unmet medical need. So our idea is that: can we use an enzyme like Palynziq, but deliver it in a way that we can overcome the immune response of the organism? And the idea is to move the enzyme into the red blood cells and deliver, not to be released from the red blood cells, because it’s the substrate of the enzyme that is passing the membrane of the red blood cells, reaching the enzyme and is cleaved. In another disease different from PKU, we have already proven in humans that that concept works. So, the idea is to deliver the enzyme through the ref blood cells and become the new way of administering enzyme replacement therapies to overcome the immune risk for the patients.

Daniel Levine: If I’m not mistaken, Palynziq is a pegylated molecule. Does pegylation affect your ability to do this?

Luca Benatti: No, we won’t use the pegylation because there is no need to pegylate the enzyme if the enzyme is protected by the red blood cells. Plus, as you probably know, pegylation itself is causing an immune response. So, while pegylation is made to protect the enzyme from the immune response, pegulation itself generates PEG antibodies, and that’s another problem.

Daniel Levine: You’re not using the marketed version of Palnyziq, but you’re developing your own, is that correct?

Luca Benatti: Yes.

Daniel Levine: I suspect you face an additional challenge getting adoption of these theories because it involves some education of providers. Is the expectation this will be sold to centers of excellence or centers that specialize in treating certain conditions?

Luca Benatti: Yeah, that is going to be mostly our plan. We are going to target infusion centers through center of excellence pediatric hospitals in the U.S. and, and that will be with an interesting, for instance, for our ataxia program, an interest in synergy there because, as I mentioned, the ataxia patients are immunocompromised and they go monthly to an infusion center to receive immunoglobulin infusions, and therefore it will be very synergistic to go to the same infusion centers and receive also the EryDex therapy once a month.

Daniel Levine: When you’ve had discussions with potential customers, what’s been the response to the technology?

Luca Benatti: Well, I think of course it’s something that people need to understand and need to be acquainted with. Of course, it is different than giving a panel to someone and saying you inject every day in leg or whatever. So there is some training, some learning that needs to be made, but what is the beauty I believe of this technology is the fact that it is a kind of personalized medicine because you use your own blood. The second thing is that it provides a lot of flexibility because of the small machine that can be installed. And maybe one can think, even in the future, if that technology becomes more widely used for other applications, that one can think also of a different distribution of the procedure and the machine and maybe in the not distant future, even a home based kind of procedure where the nurse is reaching you at home and providing you the medication. That is where we need to work on, of course, but the experience we had so far in this large phase 3 trial that I like to remind was performed not only in countries in Europe and the U.S., but also Asia and Australia, so it has been exposed to different cultures and different procedures in the hospital. We had a very efficient implementation of the procedure because it’s a very simple one. And that I think speaks in favor of yes, it’s more complicated than others, but at the end, the real world experience is already very, very encouraging

Daniel Levine: Luca Benatti, CEO of EryDel, Luca, thanks so much for your time today.

Luca Benatti: Thank you.

This transcript has been edited for clarity and readability.