The Challenges of Developing a Therapy for Pregnant Women with a Rare Condition

Hemolytic disease of the fetus and newborn is a rare autoantibody condition for which there is no approved therapy. It causes the mother’s immune system to attack and breakdown the red blood cells in her fetus or newborn. It is one of more than 10 immunological and neurological indications for which Johnson & Johnson is developing its experimental monoclonal antibody nipocalimab. We spoke to Katie Abouzahr, vice president of the autoantibody portfolio and maternal fetal disease area leader for Johnson and Johnson, about hemolytic disease of the fetus and newborn, the challenges of developing a therapy for a rare condition in pregnant women, and why nipocalimab has the potential to be a pipeline in a product.

Daniel Levine: Katie, thanks for joining us.

Katie Abouzahr: Absolutely, my pleasure, Danny. Thank you for having me.

Daniel Levine: We’re going to talk about rare autoantibody diseases, maternal fetal conditions, and Johnson & Johnson’s lead experimental therapy in this area, which has the potential to address multiple indications. Let’s start with autoantibody diseases. Can you give a sense of how big a group of conditions this encompasses and the range of conditions it includes?

Katie Abouzahr: Yeah, absolutely. Thanks so much Danny. So overall, nearly 240 million people worldwide, I believe, suffer from autoantibody driven diseases. And whilst there are maybe up to 80 different diseases that are thought to cause an autoantibody disease, many of those are rare, some of them are prevalent and most of them don’t actually have a safe, effective, approved, or targeted treatment option. So these 240 million people actually do have an immense unmet medical need. The way to think about it across these 80 different diseases is we look at the landscape in three segments. The first segment in autoantibody driven diseases is rare diseases that are directly caused by an autoantibody. The second segment that we think about in the landscape is maternal fetal immunology, diseases of pregnancy, which I think we’re going to talk a bit more about later. And then the third segment in this space is the prevalent rheumatology diseases, by and large, driven by autoantibody complex formation. So it really is quite a huge area of unmet medical needs. And we look at the landscape in those three segments when we think about it.

Daniel Levine: These diseases involve the immune system turning against the body. How much commonality is there between the conditions in terms of what triggers them, the biological pathways involved, or how they can be treated?

Katie Abouzahr: Yeah, absolutely, because I mentioned 80, and it’s hard to imagine that they have a sort of similar underlying cause. But actually, as the name would suggest, it does start with autoantibodies. So, I’m going to remind even once more and say, well, let’s start with antibodies, the most common kind of which in the body is IgG antibodies. And under normal circumstances, they protect the body from attack from various things, viruses, bacteria. But in these disease states, they turn against one’s own body and can attack critical organs and tissues. And actually, in pregnancy, maternal alloantibodies we call them, can attack organs and tissues of the fetus. So, it’s essentially antibodies that have gone rogue and are attacking oneself or one’s fetus in pregnancy, and we call them autoantibodies. So, they tend to be pathogenic IgG autoantibodies, and that one common mechanism underlies all these different diseases. And actually, as I mentioned, when we think about them in the different three segments, there are different flavors of these diseases. So, in rare autoantibody diseases it is one known autoantibody causing a disease, for example as in myasthenia gravis. And in maternal fetal immunology, as I mentioned, it’s an IgG pathogenic antibody that mum forms [against] baby. And then it’s a slightly different mechanism in prevalent rheumatology where these IgG pathogenic autoantibodies form immune complexes and those cause disease—think something like rheumatoid arthritis. But yeah, so to your point, they do have this underlying mechanism. So, I guess then when we think about how do we address it, what you really want is to be as targeted as possible in addressing the underlying cause of autoantibody diseases. And actually, one of the promising new targets in this space is a protein called the neonatal Fc, crystallizable fragment receptor, and we call it the FcRn. So, it’s a transmembrane protein. It’s present throughout life in vesicles and endothelial and immune cells. And what it normally does is bind and recycle IgGs, so antibodies, and by doing that, it keeps them in circulation because it’s recycling them. And I guess given where I was early on, the underlying cause, the research that’s emerging has shown that potentially by blocking the FcRn, you can stop the FcRn from recycling IgGs, including recycling autoantibodies, and therefore reduce pathogenic autoantibodies significantly from circulation and therefore potentially improving and modifying the diseases that are caused by these autoantibodies. And actually then the clue is in the name. So, I mentioned that it’s the Fc neonatal receptor. It was first actually discovered in syncytiotrophoblasts in the placenta, and in pregnancy by blocking the FcRn, you also block the passage in these disease states of alloantibodies from mum to baby and therefore you would prevent them from causing harm to the baby. So there’s quite a lot in that, but that’s essentially what links them all and therefore also provide this common potential pathway for treating them.

Daniel Levine: I want to focus on hemolytic diseases of the newborn, which is a maternal fetal immunological disease. But before we get into the condition itself, what happens to the immune system during pregnancy? What’s the relationship between the mother, her immune system, and the fetus and its immune system?

Katie Abouzahr: Well, actually this is an area of increasing research. I mean, traditionally way back when I was at medical school, which was quite a long time ago now, we thought of it as mum is immunosuppressed because she’s hosting baby—a bit like an organ transplants. And that was a sort of typical way of thinking about it. But what we know now is it’s far more nuanced and complex and in a way [more] elegant than that. And I’d say that we think of it more fitting to characterize pregnancy as a really unique immune state that’s modulated and that’s specific to different stages of pregnancy. And that goes both ways. So it is true that the pregnant person is hosting a baby, but in addition, the maternal immune system still does actually exhibit a strengthened network, really ensuring the wellbeing of both mom and fetus. It carries on playing a really important role in safeguarding the pregnant individual from environmental threats, preventing harm to the fetus. And actually the fetus also contributes to the development of an active immune system. And this alters in a pregnant individual’s response over time during pregnancy and it’s highly orchestrated. So I think we’ve come a long way in terms of what we know and how we think about the immune system with the pregnant person and the baby during pregnancy.

Daniel Levine: Well, what is hemolytic disease of the fetus and newborn?

Katie Abouzahr: Yeah, absolutely. So we call it HDFN for short, and it is a rare disease. Essentially what happens, as I was alluding to earlier, is that the pregnant person forms antibodies. So, we call them alloantibodies that are designed to attack something in the developing fetus. And in HDFN, it’s the fetus’s red blood cells. They’re IgG alloantibodies, they’re formed by mum, and then they would cross the Fc neonatal receptor and go and attack baby’s blood cells. And I can come onto it in a little bit, but as you can imagine with devastating consequences. Why is that happening? It’s happening because we all have different genetics, and it occurs when there’s a mismatch in the antigens that you have on your red blood cells between mom and baby, a pregnant person and their fetus. Typically, what happens is the fetus has an antigen positive inherited from the paternal side, and the pregnant person has antigen negative. So, they don’t have those antigens, but then when they see them in their circulation from baby, they recognize them as other and form antibodies to attack them. So that’s what’s happening. It isn’t ultra rare disease–in the U.S., 80 at out of every 100,000 pregnancies, and then the very severe form of HDFN, maybe five or six to around seven and a half in a 100,000 newborns every year. And it’s not uncommon actually. I would say what’s much more common [is] for a parent and their children to have incompatible blood types. But what happens in HDFN is you have this cascade where the pregnant person forms this immune response against the red blood cells and creates these alloantibodies, and we call that alloimmunization.

Daniel Levine: How does the condition manifest itself and progress?

Katie Abouzahr: So, as you can imagine, if you’ve alloimmunized and you go on to have an HDFN pregnancy where there are pathogenic alloantibodies crossing the FCRN and attacking baby’s red blood cells, as you can imagine, the symptoms can be devastating. And it’s worth noting that typically in the third trimester of pregnancy, the pregnant individual and their baby are in equilibrium in terms of IgGs or antibodies in circulation. And so, you have all these maternal alloantibodies in fetal circulation. And actually, one of the things we know about HDFN is that it gets worse with every single pregnancy because you have the memory of making more and more of these alloantibodies. So, you’re attacking red blood cells—so mild anemia could be, babies can be hyperbilirubinemic and therefore develop jaundice, and it can progressively be more severe. They can get more severe anemia, they can get hydrops fatalis (severe swelling), and in severe HDFN, it can result in fetal demise because, if you think about it, destroying baby’s red blood cells obviously can have devastating consequences. I mean, apart from that, it just causes significant complications around the time of birth and then also in the neonate.

Daniel Levine: And how is it generally diagnosed?

Katie Abouzahr: So, with HDFN, we do know what are the mismatches in red blood cell antigens that can cause it. I mean typically it’s ABO and then also Rhesus D, although there are many others. And so, you can do a blood test to see if the mother has incompatibility with the fetus and to see if the pregnant person has developed alloantibodies. However, you do have to have access to antenatal care. And if you have good access to antenatal care and you happen to get the right blood cell tests and you have not yet alloimmunized, you’ve not yet started to form these alloantibodies, then actually you can be given RhoGAM to prevent alloimmunization in that pregnancy. But if you don’t have access, or for whatever reason you’ve already alloimmunized, for example, [through] a blood transfusion or trauma or a previous pregnancy that you didn’t know about, then there are no available therapies. Once you have alloimmunized, what typically happens is the first pregnancy it will be very mild or not clinically detectable, but then with each subsequent pregnancy, once you’ve alloimmunized and you start to develop HDFN, there are no therapeutic non-invasive treatments. Actually, it really does highlight the importance of awareness of these rare diseases, of really good antenatal care being available, to try and ensure that women and their families are getting access to the care they need.

Daniel Levine: What treatment options exist today for the condition and what’s the prognosis for someone with it?

Katie Abouzahr: As I mentioned, if a pregnant person has alloimmunized, there are no approved therapeutics and every single pregnancy becomes more severe than the previous one. And in severe HDFN, because there’s no treatment, all you can do is monitor. And then once the baby has started to manifest symptoms of HDFN, so intrauterine growth retardation, then really the only option is to perform a very risky and invasive surgical procedure, which is an intrauterine transfusion and IUT. It requires access to specialty care, and it is, even in the best hand, it carries risk. It involves passing a needle through the pregnant person’s belly and infusing blood directly into fetal circulation, and it has to be done in a timely manner in specialist centers. Of course, as you can imagine, an extremely challenging, risky, stressful procedure for families. And so even then, severe HDFN does cause significant fetal mortality and complications. So there’s a huge unmet need for a safe and effective non-invasive treatment option that’s targeted at the underlying disease.

Daniel Levine: Johnson & Johnson’s lead experimental therapy in this area is nipocalimab. What is nipocalimab?

Katie Abouzahr: So, it is a very purposefully designed anti-FcRn. It binds to very tightly and inhibits or stops the actions of the Fc neonatal receptor, and therefore it has two effects. It prevents the FcRn from recycling IgGs and therefore they reduce out of circulation very significantly. And then of course in pregnancy as we’ve been talking [about], it prevents IgGs including auto and alloantibodies from passing across the Fc neonatal receptor from the pregnant person to their developing fetus. What is it in and of itself? It’s actually a fully human monoclonal antibody that’s been specifically designed to block the FcRn and reduce the circulating IgGs. And it is in fact an IgG-1 scaffold itself. In thinking about the design, also, it’s been carefully designed to be very selective. It binds very specifically where an IgG would normally bind on the FcRn receptor and it binds incredibly tightly, both in the endosome where recycling happens, but also at the cell surface, so neutral pH so it does not cross into fetal circulation is the belief around how we’re developing it.

Daniel Levine: One of the things that really interested me about this drug is how you do clinical trials for it. It’s being studied in women who are at risk for developing hemolytic disease of the fetus, but finding participants for a rare disease clinical trial is challenging on its own. I think of most studies excluding pregnant women. What’s it like to enroll a study of pregnant women for a rare condition? What challenges does that create and what safety concerns need to be addressed?

Katie Abouzahr: Yeah, absolutely. It’s a great question. We are studying nipocalimab actually in all three of the segments of autoantibody driven disease I mentioned earlier, and we are the only company developing any therapeutics in the maternal fetal immunology space for diseases like HDFN where there’s so much unmet medical need. And you are absolutely right, it’s not often done. And in fact, this is a sort of area that hasn’t traditionally had the focus that it deserves in terms of research into therapeutics. And in fact, if you look at all the clinical trials at any one point, less than 1 percent contain the word pregnancy. So, there’s been a long history of trepidation or fear around pursuing research in this space. It’s a delicate area. It involves two patients, the fetus and the pregnant individual. And by not having been studied, you create a vicious cycle where it becomes even more challenging to then go into it. I would say a couple things. I mean, first of all, I’m sure you’ll have seen that we have had vaccines now specifically approved for pregnant women. And I think there’s an increasing recognition globally of the need for robust clinical evidence-based research in this space to provide individuals and their families with the right therapies to treat the right diseases that have been studied for approval in these cases. So I think there is a sort of macro environment where things are moving. I will say I’m speaking for myself, but I hope and I believe I speak for the whole rest of the team, that we have a huge amount of passion around addressing the gap in therapeutics in this area. And we feel really strongly that there is unmet medical need that we believe we have the ability to potentially address. We go into it eyes wide open. We talked earlier, these are rare diseases. There’s the inherent challenges of rare diseases and how you think about enrolling these. Of course, you’re always thinking about the inherent challenges of the disease itself. So, you need to keep in mind that, as you design these studies. But we have been really intentional about listening to the experts in the maternal fetal medicine space, about building on our long history of drug developments in immunology, of listening to patients and understanding their concerns, and of bringing all those things together and of also talking to and partnering with the regulatory agencies as we go forward to make sure that we are bringing forward the best possible development program to meet patients’ needs.

Daniel Levine: Earlier this year, Johnson & Johnson reported positive results from a phase 2 study of nipocalimab in hemolytic disease of the fetus and newborn. What’s known about its safety and efficacy from studies that have been conducted to date.

Katie Abouzahr: Yeah, so we indeed did, we shared the results from our phase 2 Unity study, and that was a study of patients at risk for severe HDFN who received nipocalimab. The primary endpoint in that study was live births at or beyond gestational age of 32 weeks without the need for single intrauterine transfusions throughout their pregnancy. And actually, what we did, and you’ll have seen in the press release, is that we looked at the historical benchmarks and we believe that in pregnant patients at high risk for severe HDFN, so these are patients who have had a previous pregnancy where they had severe HDFN, the historical benchmark for hitting that primary endpoint, we believe, is around 10 percent. And in Unity, actually the majority of pregnant patients at high risk for severe HDFN were able to hit the primary endpoint and achieve a live birth after gestational age of 32 weeks without an IUT, it was 54 percent in the study. So obviously we think that’s a really exciting potential development for patients with HDFN, and we look forward to moving into a pivotal phase 3 trial, it’s called AZALEA, in order to assess the effectiveness of nipocalimab compared to placebo in pregnant participants at risk of severe HDFN as well. So those were the results in the study that we’ve done so far in HDFN. I mentioned earlier that we are studying all three segments of autoantibody driven disease, so rare autoantibody diseases like myasthenia gravis, maternal fetal immunology, which we just talked about HDFN, and also prevalent rheumatology. And actually, nipocalimab has also demonstrated proof of mechanism with efficacy and safety and other phase 2 studies. So, in our phase 2a IRIS study in rheumatoid arthritis, we showed proof of mechanism, which is actually the first time that efficacy is shown using this mechanism in this disease—removing autoantibodies specifically. And then we already had the data from our phase 2 study of nipocalimab in our rare autoantibody indication of myasthenia gravis, where again, we showed rapid deep sustained clinical response versus placebo. I guess thinking about the wider auto-anti landscape, going back to where we started with how to think about the autoantibody driven diseases and these three segments, we do now have proof of concept, proof of mechanism, in all three of these segments with nipocalimab.

Daniel Levine: This is one of those pipeline in a product opportunities. How broadly are you thinking about nipocalimab and how are you going about prioritizing indications you’ll pursue?

Katie Abouzahr: It’s a great question because I mentioned 80, right? So absolutely we are prioritized. But yeah, you mentioned pipeline in a product. You’re absolutely right because this has a pathway centric strategy at its core. So, it selectively removes IgGs, but pathogenic IgGs underlie so many different diseases that this pathway approach, even though it’s very selective in that disease, does actually allow you to potentially treat a huge number of different autoantibody driven diseases. We have been very careful and thoughtful and systematically assessed autoantibody and alloimmune driven diseases and prioritized 10. And we do this–we are driven by the science first and foremost–so we prioritized 10 where the actionable science was clear and with the highest unmet patient needs and where we are building on Johnson & Johnson’s core strengths in areas that we know in immunology and neuroscience. And that’s the way we landed on these 10 that do fall across all three segments of autoantibody driven disease. The way we think about nipocalimab across the three segments is in rare diseases, as I mentioned, those that are directly mediated by a known autoantibody, so myasthenia gravis, and that’s anticipated to be our first indication to launch. We’re also looking at warm autoimmune hemolytic anemia, and then in the rheumatology space, idiopathic inflammatory myopathies, and then in neuroscience, chronic inflammatory demyelinating polyneuropathy, and in dermatology, bullous pemphigoid. And those five clearly prioritized, as I mentioned, actionable signs, unmet need. Then in maternal fetal immunology, hemolytic disease of the fetus and newborn. And then we’re also looking at an alloimmune disease of pregnancy where the pregnant individual forms alloantibodies to the baby’s platelets, and that’s fetal neonatal alloimmune thrombocytopenia. And then finally that third segment with that slightly different mechanism of autoantibody complex formation, rheumatoid arthritis. I mentioned, we are looking at that in a combination of nipocalimab and another therapeutic there. This is a disease where there are approved advanced therapies, but many patients remain refractory to them. And then also systemic lupus erythematosus and Sjogren’s disease. So that takes you to 10 in total, really leveraging our deep disease understanding and our deep understanding of the mechanism in this pathway centric approach.

Daniel Levine: Katie Abouzahr, vice president of Autoantibody portfolio and Maternal Fetal Disease area leader at Johnson & Johnson. Katie, thanks so much for your time today.

Katie Abouzahr: A pleasure, thank you for having me.

This transcript has been edited for clarity and readability.