Disabling Antibodies that Drive Rare, Immunological Conditions

Antibodies play an important role in the protective immune response. In some situations, though, such as autoimmune diseases, antibodies can cause harm by attacking healthy tissue. Hansa Biopharma has developed an antibody-cleaving enzyme technology platform to target pathogenic antibodies involved in autoimmune disease, organ transplantation, and gene therapies. Its lead experimental therapy, imlifidase, is designed to inactivate immunoglobulin G antibodies through a single intravenous treatment. It is in development for a range of rare, immunological conditions including Guillain-Barre syndrome or anti-GBM disease and as a pre-treatment for various gene therapies. We spoke to Matthew Shaulis, chief commercial officer and U.S. president for Hansa Biopharma, about the company’s antibody-cleaving platform technology, how it works, and its range of potential uses.

Daniel Levine: Matt, thanks for joining us.

Matt Shaulis: Hey, , it’s all our pleasure, Danny. Really appreciate you having us.

Daniel Levine: We’re going to talk about Hansa, its efforts to inhibit immune responses, and why beyond autoimmune conditions this can have a significant role in enabling patients to receive gene therapies. Perhaps we can start with immunoglobulin G. For listeners not familiar with this, what is it? What’s its role in the immune system?

Matt Shaulis: Yeah, great question, Danny. I’ll start out with an overall explanation and then maybe provide an answer to, along with an analog. Antibodies, and in particular, immunoglobulin G, also known as IgG, are an important element of the protective immune response. When a foreign organism, such as a bacteria or a virus enters the body, IgGs can recognize and bind structures on its surface, which we all, of course, know as antigens and alert the cells of the immune system to attack and eliminate the foreign organism. In some situations, IgG can become harmful. They can act as a barrier preventing a patient from receiving life altering therapies such as organ transplantation or gene therapy. In transplantation, for example, antibodies identify the transplanted organ as a foreign body and trigger a targeted response of the immune system against it. This causes damage and potentially the loss of the graft because, in essence, the IgG antibodies attach to the antigens on the donor organ and mount a coordinated attack from the host immune system onto that donor organ. Examples of donor specific antibodies acting on donor kidneys are numerous, and they can lead to what’s known as antibody-mediated rejection of that graft organ, and these include preformed DSAs in sensitized patients that can trigger various forms of antibody-mediated rejection. One analog would be a defender that is not only protecting a fortress from foreign attackers, but a defender that’s already familiar with that foreign attacker and is quick to recognize them and able to dispatch them more effectively and expeditiously. So, due to the speed and the effectiveness of this defense, an intervention is needed to stop the defender from destroying that foreign body, which in the case of a transplant might be a foreign and beneficial emissary rather than an attacker. IgG can, in some cases, activate the immune system against the body itself rather than a foreign body, for example, in autoimmune conditions. And one prime example of this is anti-GBM, or anti-glomerular basement membrane, disease when antibodies directed against a particular type of collagen in the filtering units in the kidneys and the tiny air sac in the lungs lead to rapidly worsening disease. Fortunately, once treated, this immune attack rarely comes back, and to carry over our earlier analogy, this would be like the fortress defender erroneously attacking its own people by wrongly identifying them as foreign. So, I went a little bit deep there Danny, with both the mechanism and some examples, but I thought that might be a useful way to lay things out upfront.

Daniel Levine: Well, you’re developing—you’ve won approval in Europe for a therapy that treats—it’s a pre-treatment for highly sensitized adults prior to kidney transplantation. You’ve got a group of rare diseases that are autoimmune that you’re also working to develop therapy for. And this is also a potential pretreatment for gene therapy. In all these cases, is the underlying biologic mechanism the same?

Matt Shaulis: Essentially, the idea of imlifidase acting to cleave IgG is the core principle that unifies all of them, and then ultimately there are different applications to that, right? So, in the case of kidney transplantation it’s cleaving these antibodies that would otherwise lead to the rejection of the graft. In the case of the autoimmune diseases, it’s cleaving the IgG antibodies that would otherwise attack own tissue. And then of course, in gene therapy, what the treatment is able to do is cleave those antibodies that would attack the viral vector that carries the gene therapy into the cell. So, essentially one mechanism with multiple different applications. This is one of those platforms where the more we know about it, the more we understand potential applications for it.

Daniel Levine: In the case of gene therapies, what percentage of patients actually generate an immune response to a viral vector?

Matt Shaulis: Yeah, this is a great question, Danny, and I think you hit on the key concept here, which is that the immune system essentially is doing its job by defending the body from that viral vector, even though in this case, the viral vector is fairly benign as it’s carrying the genes. Essentially this leads to another coordinated attack on another known foreign body, the viral vector. As for overall incidence and prevalence, it varies by viral vector. So, around 30 to 60 percent of patients are unable to use gene therapies because of these pre-existing antibodies to the adeno-associated virus vector used to deliver them. It’s also important to know that there are several AAVs, as they’re known, being tested now to deliver gene therapies. Let me give you a couple examples. I’ll start with Duchenne muscular dystrophy gene therapies. They currently use AAV-RH74 and AAV9 and observe neutralizing antibodies in approximately 30 percent of patients. In this case, about 20,000 patients each year suffer from Duchenne muscular dystrophy. Hansa has a collaboration with Sarepta Therapeutics to study in imlifidase as a pre-treatment with Elevidys, which is Sarepta’s recently approved Duchenne muscular dystrophy therapeutic, which in this case is carried by AAV-RH74. A second example would be gene therapies for Pompe disease which are carried by AA8, and neutralizing antibodies are observed in up to 60 percent of these patients. Approximately 10,000 patients each year suffer from this debilitating illness, and Hansa is exploring opportunities to enable gene therapy in this space as well.

Daniel Levine: In the case of patients that do have antibodies against these vectors, I take it the issue is the immune system destroys the vector before the payload is able to reach the cells that it needs to go.

Matt Shaulis: Yeah, ultimately that’s the challenge. And certainly, this challenge, you know, began to emerge in the clinical trial setting when gene therapy companies were essentially trying to identify the right set of patients to go into the studies and came to learn that this can be a barrier. But now I think there’s a better opportunity to understand, even beyond that trial setting in clinical practice, how often this barrier to treatment ends up arising. And while there is a fairly substantial range in the occurrence of these neutralizing antibodies, as I mentioned a little bit earlier, it’s about 30 to 60 percent in clinical application, and it’s really driven, as you said, by the viral vector. It’s not so much the underlying disease or the payload of the gene. It’s really the viral vector that the immune system recognizes. So, we’re really excited about what this might be able to do for patients that otherwise wouldn’t have an opportunity to access these kinds of transformational treatments.

Daniel Levine: The other issue with viral vectors is that even if a patient doesn’t have pre-existing antibodies against them, they’ll develop them once they’re treated. And that goes to the issue of durability and the ability to re-dose patients. Does this have the potential to make gene therapies redosable?

Matt Shaulis: I think that that’s an exciting area where we’re going to need to generate more data and really understand the applicability. I can talk through a couple of different examples where recently we’ve started to explore the possibilities. There’s certainly a potential for short-interval dosing or re-dosing when a gene therapy that’s lower for a safety reason may need to be re-administered again within a few days or within a week or so to achieve the adequate level of efficacy. That’s one example. Another is long interval re-dosing where a pediatric or adolescent patient may need to be re-dosed years later in order to sustain the efficacy and the benefit of the gene therapy. So, in these examples of both short and long interval re-dosing, there’s a potential opportunity for our next generation molecule known as 5487 to be a part of repeat dosing. And of course, we need to generate more data in this setting, but one of the principle advantages of 5487 is that it’s essentially designed to be able to enable repeat dosing. So, we’re really excited about the potential to see more data and see what this might be able to do for patients. And of course, consistent with the nature of your question, this goes beyond that simple concept of pre-treatment and really explores a broader therapeutic opportunity.

Daniel Levine: Your lead experimental therapy imlifidase is in development for all of these conditions. We’ve talked about this that it is actually a bacterial enzyme. How was it discovered?

Matt Shaulis: Imlifidase is actually a really interesting molecule. It’s like the more we look at it and consider different applications, the more that we find, and perhaps this is in large part because imlifidase has a very simple and highly effective mechanism of action. Imlifidase, as you said, is indeed a bacterial enzyme. It was discovered in Lund, Sweden at the University located in Lund. And scientists discovered that the bacterial family streptococci protects itself against an immune attack from the host by producing a specific enzyme that targets and cleaves IgG. So given the unique specific ability of the enzyme, researchers began to consider what applications it might be useful in, and the research gave way to the creation of Hansa and then the advancement of imlifidase for several different conditions. And of course, we referenced today kidney transplantation, autoimmune conditions, and of course gene therapy.

Daniel Levine: We’ve seen bacterial enzymes used therapeutically before, certainly with Crispr, and people are getting accustomed to that thought. we’ve got a PKU therapy that’s actually a bacterial enzyme. Is there any risk though of the enzyme itself generating an immune response?

Matt Shaulis: Yeah, it’s a great question, particularly given what we know about the immune system. What’s important to think about here really are two things. First, imlifidase specifically targets IgG, it’s unique mechanism of action is highly specific to work only on IgG. It will only deplete or attack IgG. Second, we know from our clinical trials that one dose of imlifidase is safe and effective and doesn’t trigger a problematic immune response. We’re also working, as I mentioned a little bit earlier, on the next generation of our IgG cleaving enzyme to hopefully develop a therapy that can be used repeatedly. This molecule, which is in early stages of clinical development, is known as 5487. It could be beneficial in areas where repeat use or combination therapy would be beneficial. And of course, one of the areas that that we’ve designed for and that we’ll be closely monitoring and studying in those early stage clinical trials is, in fact, that immune response. But right now, we’re confident that that we’re going to end up seeing a really promising treatment option here.

Daniel Levine: IgG actually has an important role within the immune system. Is there any concerns about targeting it in these autoimmune conditions with repeated doses, and dampening the immune system in ways it needs to be able to function?

Matt Shaulis: Yeah, I think thus far across a multitude of different disease settings where we’ve studied the molecule, we haven’t seen any of those adverse, bigger system systemic issues related to the immune system and overall responses. Naturally this is an area of real expertise for the company. It’s something that we monitor very closely and we’ll continue to keep an eye on that. But across some of those settings, including kidney transplantation, GBS, anti-GBM, and now the early stage first in human studies for 5487, we’ve not yet seen those issues and the overall robust evidence package for, imlifidase continues to be a real strength in the molecule.

Daniel Levine: Well, what’s known about it from the safety and efficacy studies that have been done to date?

Matt Shaulis: I think thus far, when we’ve looked at the safety and efficacy studies of the molecule, particularly as a pretreatment in kidney transplantation to reduce donor specific IgG, we’ve seen a consistent efficacy and safety profile. There have been four phase 2 open label, single arm six-month clinical trials, and then in additional clinical trials of imlifidase, there were also no major adverse events. We see this similar safety and tolerability results in clinical trials that include GBS, and we have an ongoing phase 3 trial in anti-GBM that builds on earlier trial experience in that same disease setting. So, this is important as it might mean that imlifidase could continue to demonstrate this consistent safety profile across different indications.

Daniel Levine: This is a significant partnering opportunity for Hansa in the area of gene therapy. It’s partnered with Sarepta, you already mentioned also with AskBio and Genethon. How do you think about Hansa’s partnering strategy in terms of its ability to fully realize the value of imlifidase?

Matt Shaulis: Yeah, another great question, Danny. Strategic partnerships with gene therapy companies are an important opportunity to advance the science in these areas where there’s really high unmet need with little to no approved treatment options. And our hope is that these partnerships will help advance the understanding of these conditions and potentially find new approaches to care, including how imlifidase may be used as a pre-treatment to gene therapy. Ultimately imlifidase and potentially 5487, our next generation molecule, may be able to help patients receive these critical, in many cases, life-altering and life-saving treatments, while at the same time enabling a treatment opportunity for a gene therapy product and a company that might otherwise be prevented from benefiting that patient because of the neutralizing antibodies. There’s also some other areas where we’ll explore opportunities for combination treatment in autoimmune disease, and this could be a little bit different than pretreatment. The combination therapy could be something that would ultimately lead to a greater benefit for patients with rare autoimmune conditions. And this could be areas like myasthenia gravis or ITP where we’re looking at a couple different mechanisms that we might combine with, or an autoimmune CNS disease where we might look at combinations with IL-6 or CD-19 agents for a host of different conditions. So, we think that the opportunities for partnership and pre-treatment or combination could be fairly broad. And again, given the safety and efficacy profile that we’ve seen in earlier studies, we think that the profile of the molecule really lends itself to some of this wider applicability.

Daniel Levine: You’re not alone in seeking to develop an immune modulating therapy to prevent an immune response to gene therapies. In fact, Sarepta’s been working with Selecta Biosciences in both Duchenne and limb girdle muscular dystrophy. Any sense how your approach compares to other approaches?

Matt Shaulis: Yeah, right now Danny, there’s an incredible amount of research and discovery happening in the immune modulating therapy space. This is important and really exciting work, given the potential that it has for patients. What makes imlifidase different is its MOA, it specifically targets only IgG antibodies. It cleaves or depletes them almost entirely in a very short period of time. We ultimately have evidence in a pretty substantial body that shows it works and has this consistent safety profile across different clinical settings in our trials. And we believe we have solid evidence that’s been, in some cases, reviewed and looked favorably upon by regulatory bodies, including in the EU and Australia. This supports the efficacy and safety of the molecule based on that review that was done by some of these respected regulatory bodies. And in addition to the clinical data that’s been reviewed, we’ve also been able to scale up to commercial supply levels and produce imlifidase in a reliable and consistent form with manufacturing that’s also been reviewed and ultimately validated by those regulatory bodies. So, I can’t really speak to the other approaches, and I understand that many of the molecules in this space are in very early clinical development and obviously would then have other steps related to CMC and supply that would that have to follow later.

Daniel Levine: When I think of the use of this in gene therapy, it brought to mind early days of precision medicine with companion diagnostics and the gulf between the diagnostic makers and the drug makers over how to value the combined product. The drugs couldn’t be used without them and at the same time, pharmaceutical companies looked at their drug as having most if not all of the value. How does it work with imlifidase? Do you control the pricing and market it separately from your partner, or will it be packaged and sold as one and the same as a gene therapy?

Matt Shaulis: Yeah, it’s a great question, Danny, and I can certainly comment on some of our strategic intent here, and I see the logic of the analogy that you’re making with diagnostics. It’s an excellent perceptive observation. Well, ultimately, in this case, imlifidase has an MOA that enables the efficacy and safety of transplantation or treatment in the case of gene therapy or directly intervenes with the underlying disease in the case of some of those autoimmune conditions. So, ultimately, it’s a direct treatment itself with a clinical utility that goes beyond diagnosis. Constant controls and our strategic intent will continue to be pricing and commercialization of imlifidase. We have a phase 3 trial in kidney transplant desensitization that’s ongoing. And while we don’t yet have a price for imlifidase in the U.S. in any indication, it’s important to note that patients that do successfully engraft a transplant and kidney no longer require dialysis, which in the U.S. on average costs the insurer and healthcare system in excess of a hundred thousand dollars a year. And these patients, in many cases, will continue to receive that dialysis for many years to come. So, there’s a substantial outcome benefit to patients and an economic benefit to the public and private payers and society at large when that need for continued dialysis is obviated. So, strategically Hansa’s approach to pricing is one that’s based on a deep understanding of value of imlifidase to address that unmet need to the patient as well as to provide value to healthcare systems and society at large. And similarly in gene therapy, we’ll work closely with our partners to ensure that there’s appropriate pricing and accessibility for appropriate patients while again, retaining that control of pricing and commercialization ourselves.

Daniel Levine: You think of both gene therapy and kidney transplants as being very expensive treatments. As you look more broadly for a therapy that could have such broad implications, is there some concerns about how you price it given all the different markets it could be useful in?

Matt Shaulis: Yeah, absolutely, Danny, that’s something for us to be attentive to. I think our goal as a company is to ensure that we work with all the right pricing authorities and public and private payers in a thoughtful way to ensure that we can bring the benefit of imlifidase and then in time 5487 really to the patient populations that need the treatment. We’ll not only look at the opportunity across different indications, but also across different markets and ultimately do what we think is in the best interest of access overall.

Daniel Levine: Matt Shaulis, chief commercial officer and U.S. president for Hansa Biopharma. Matt, thanks so much for your time today.

Matt Shaulis: Danny, it was a real pleasure. Thanks for having us and look forward to any future engagement.

This transcript has been edited for clarity and readability.