Finding the North Star of therapeutic antibodies

Listen to this article on the DDW Podcast: Katie Abouzahr is the Vice President, Autoantibody Portfolio and Maternal Fetal Disease Area Leader at the Janssen Pharmaceutical Companies of Johnson & Johnson. She speaks with Megan Thomas about the future for Janssen’s investigational medicine nipocalimab and antibody therapeutics at large. A day in the life On a day-to-day basis, Katie Abouzahr is accountable for and leads the development globally of all the assets in Janssen’s Autoantibody portfolio in immunology. Notably, that includes nipocalimab. This is a fully human monoclonal antibody (mAb) which selectively binds to the FcRn receptor with high-affinity and blocks it, thus leading to a decrease in IgG autoantibodies. Nipocalimab, according to Abouzahr, is currently the only FcRn being studied in all three segments of autoantibody-driven disease. Moreover, Janssen has ten prioritised indications across maternal foetal, rare autoantibody, and prevalent rheumatology. Abouzahr explains: “In terms of day-to-day life, it varies significantly depending on what the needs are across the programme, or where we are in specific areas. I try hard to prioritise my efforts as to where I lean in with the team. It ranges from setting a strategic direction, all the way through to successful operational delivery of a specific programme or indication. I am constantly in contact with the team to make sure I'm on top of the latest status of our programmes, I'm thinking about next steps, and as you can imagine, it's a mixture of meetings in person, virtually, emails, conferences… So, the full gamut, which I love, because no day is ever the same. But if I think about what is the North Star, or what guides where I put my time, it’s: how do we bring this new medicine to patients in need? Is what I’m doing now going to materially enable that?” Innovation and evolution Abouzahr says that we are seeing incredible advancements in the development of therapeutic antibodies to treat diseases, which she attributes to a growing understanding of the immune system and its mechanisms, which we can bring together. She says: “At Janssen, we're fortunate that we're building on a leadership that we've created over the last couple of decades of treating immune-mediated diseases. What I think we're doing in the portfolio that I lead is applying that deep understanding and leadership to addressing this specific area where there's so much unmet need, which is autoantibody-driven diseases.” These, she explains are caused by pathogenic antibodies and tend to be IgG’s that are made by one's own body and attack organs and tissues. They also occur in pregnant individuals, called alloantibodies, where maternal alloantibodies can cross the placenta and cause harm to the developing foetus. She adds: “It's a version of your immune system responding abnormally, so instead of turning on viruses, bacteria is turning on oneself, and it can be lethal. There are approximately 80 chronic autoimmune or acute alloimmune conditions. They span rare and prevalent. As I mentioned, they're across three pillars in terms of how we think of them - maternal foetal like haemolytic disease of the foetus and newborn (HDFN), rare autoantibody like myasthenia gravis (MG), prevalent rheumatology like rheumatoid arthritis (RA). But maybe the most important thing is the approximately 240 million people – that's 2-3% of the world's population – of which the vast majority have limited safe, effective, approved, let alone targeted treatments. If I think back to the North Star, that’s how the team really approaches this.” In terms of advancing how we think about doing this, Janssen has a pathway-centric development strategy, which takes a deep understanding of the immune system and of the diseases and uses it to identify a common pathway, then the team pursues medicines that can modulate that pathway and can potentially treat multiple diseases with one therapy. Abouzahr says: “The one that's probably front of mind for most people is nipocalimab, which is our anti-FcRn pathway approach to around ten indications that are autoantibody-driven. Nipocalimab is a neonatal FC receptor blocker. Actually, ours is uniquely engineered to bind really tightly to the FcRn receptor, which leads to rapid, deep, sustained lowering of IgG and auto and allo antibodies. That allows you to go after auto and alloantibody-driven conditions. Partly because of the way nipocalimab binds so tightly at different pHs, it is the only drug currently being studied in maternal foetal, rare autoantibody and prevalent rheumatology. There are so many advancements and all of that allows us to really try and bring new medicines forward for patients who need it the most.” Opportunity and the future Thinking about where we are now and where we want to get to for the antibody market, Abouzahr explains: “For most autoantibody-driven diseases, physicians and patients end up with approaches that are perhaps nonspecific, haven't been developed specifically for that indication, or have insufficient or inadequate efficacy and/or safety and tolerability challenges. So, what we really want is for treatment to be safe, effective, approved and targeted. When you're trying to think about what the opportunity is, it's across all four of those, and so back to our North Star: how can we bring this forward for patients?” From a programme perspective, there are two opportunities that are particularly exciting for Abouzahr. The first, is that Janssen has the only experimental therapy in development for the treatment of alloimmunised pregnant adults at risk of severe HDFN, an immense unmet need for women and their families which, in severe cases, can result in foetal demise. Abouzahr says: “We are really excited about the potential for nipocalimab here, building on some of the early results that we've disclosed already.” The second cause for excitement is at the other end of the spectrum. Abouzahr comments: “Moving from something ultra-rare with no treatment options to something prevalent, where there are a huge number of patients who, despite advanced therapy, are not experiencing remission... Here, I'm talking about patients with moderate to severe rheumatoid arthritis, where again, nipocalimab is the only FcRn in development there. We look forward to disclosing some results at the end of the year. So at either end of the prevalence spectrum, there is so much opportunity and so much excitement for what we might be able to do.” The potential of antibody engineering “Antibody engineering has a transformational effect on drug discovery and how we treat diseases,” says Abouzahr. She continues: “If you just think about some of the evolution, even just looking at Janssen really transforming treatment paradigms. I guess if I look ahead to what's next, what we're starting to see and again embodied a little bit in nipocalimab is a move towards restoring immune homeostasis and immune balance instead of just broad immune suppression. So, for example, nipocalimab is a relatively targeted therapy that takes out circulating IgG and autoantibodies, but it doesn't impact wider immune system processes. So, it's more about restoring homeostasis, and it's a more targeted approach. So that, I think, is the first place that we're really thinking about what's next.” Another place is treatment modalities. Abouzahr continues: “Typically, these have been, in the antibody space, injectable monotherapies. But we're starting to look ahead to the full range of modalities. So novel tissue directed and systemic orals, combination therapy to really get at those sorts of patient populations who haven't yet responded to previous advanced therapies, like in inflammatory bowel disease (IBD). So, I think those are some of the things that we've got to look forward to, ultimately in the service of patients and going back to: safe, effective, targeted, approved.” Tailoring to a disease So, where is the mAb discovery and analysis market heading? Abouzahr reiterates that, as we get better understanding of autoantibodies, we continue to get more targeted. She said that she thinks therapies with very high specificity and an affinity for specific targets are where we are heading. “With nipocalimab, for example, the goal is to take out the autoantibodies, but wider immune function is maintained. I think that is a way of bringing precision and effectiveness. If I was a patient, that's what I’d want. I’d want something more tailored to my disease.” There is even greater ambition with precision medicine. Abouzahr says: “We talk about it, but I do think we're getting there with these personalised therapeutic approaches, where again, you're tailoring your treatment, not only now to a disease but to specific patients who may have that disease, who may have specific variations in their genes or the environment or how the disease manifests in them, thinking about biomarkers and things like that. You’re narrowing in on what you can do for patients in a more targeted, effective way, specifically approved for their condition.” The next ten years At the most macro level, the main drivers and challenges over the next ten years will be the standard challenges of drug development, according to Abouzahr. She says: “It's complex, it’s complicated - as it should be. We should be doing this in a judicious, careful, thoughtful way that is appropriately challenged. We have this immense drive to bring medicines to patients but there has to be balance with doing it thoughtfully and carefully. Drug development has always been, and will remain complex and challenging, but an incredibly worthwhile undertaking.” She continues: “As we move into some of the diseases that haven't been studied before, which is, a lot of the time, where the unmet need is, it becomes challenging to be innovative. New indications are sort of ‘uncharted’ by definition, and I think that will increase as we go forward, be it in something new and ultra-rare, or in something where we're moving towards the patients who haven't yet responded to advanced therapies.” Abouzahr says that ultimately, it’s about repeatedly asking why her team gets out of bed each day and remembering it’s about helping those with HDFN, or individuals affected by something like systemic lupus erythematosus, which disproportionately affects women and people of colour. She adds: “If you keep in mind that you could bring forward safe, effective, approved, targeted treatment options, then no matter how complex it is, or how challenging, you will get there in the end.” DDW Volume 24 – Issue 3, Summer 2023 – Therapeutic Antibody Guide Biography: Katie Abouzahr, MD, is Vice President, Autoantibody Portfolio and Maternal Fetal Disease Area Leader at Janssen Research and Development (R&D). Prior to her work at Janssen, Abouzahr served as a Principal at the Boston Consulting Group in London and Philadelphia for 12 years. Prior to that, she practiced as a medical doctor for the National Health Service (NHS) in London.