Pregnancy In Clinical Trials: Janssen Accepts The Challenge, Sees Value Beyond Maternal-Fetal Health

A conversation with Katie Abouzahr, MD, VP, autoantibody portfolio and maternal fetal immunology disease area leader, Janssen Research & Development, LLC, a Johnson & Johnson company

Navigating the intersection of rare disease research in a patient population of pregnant individuals can be tricky to say the least. With safety, efficacy, and patient centricity in mind, Janssen is taking the challenge head on with UNITY — a global, multicenter, open-label, non-blinded Phase 2 clinical trial designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of nipocalimab for the treatment of pregnant individuals at high risk for early-onset severe hemolytic disease of the fetus and newborn (HDFN).

Katie Abouzahr, MD leads the development of assets in the autoantibody (AAb) pathway portfolio and maternal-fetal immunology disease area, which includes Janssen’s lead investigative asset, nipocalimab, to address auto and alloantibody-driven diseases in multiple indications across three segments of AAb disease: maternal-fetal, rare autoantibody, and prevalent rheumatology.

Here, Abouzahr discusses the nuances of enrolling and supporting pregnant participants in clinical trials and considerations for future maternal-fetal disease research.

How has drug discovery evolved over the past few decades in maternal-fetal diseases?

Nearly 240 million people, or around 3% of the world’s population, suffer from auto- or alloantibody-driven diseases, most of which do not have safe, effective, targeted, approved therapies, and many of which are rare. These include the maternal-fetal diseases of pregnancy like HDFN. Janssen hopes to lead a much-needed and overdue transformation in this space.

HDFN is a rare disease that occurs when maternal antibodies, or alloantibodies, produced in a pregnant person’s immune system, cross the placenta and attack fetal red blood cells causing fetal hemolysis leading to anemia. The severe form of HDFN, which is categorized as an ultra-rare disease, can lead to hydrops and can even be life threatening.

Today, there are no approved therapeutics for the treatment of HDFN, and pregnancies affected by the severe form of HDFN may necessitate invasive, technically complex, and risky surgical procedures called intrauterine transfusions (or IUTs).

Indeed, only a very small number of medicines have ever been approved in the maternal-fetal medicine space, not just maternal-fetal immunology. This is something that's incredibly real for women and their families and, as a mother myself, I am passionate about addressing this gap.

How would you describe the current landscape and need for clinical trials in maternal-fetal health?

There is still a significant unmet need for clinical trials in the maternal-fetal health space. Most notably, while clinical research is critical to advancing maternal-fetal health, only 1% of clinical trials include “pregnant” or “pregnancy” in the description, according to the Coalition to Advance Maternal Therapeutics. Today, Janssen is the only pharmaceutical company pursuing clinical research regarding new treatments like nipocalimab for pregnant individuals at risk for severe HDFN.

There is a long history of fear around pursuing research in this space as it is such a delicate area that involves two patients — the fetus and the pregnant individual. However, because of this fear that stems from both researchers and patients, we have ended up with an immense unmet need in this field, and the trepidation of not “doing no harm” has potentially done harm in and of itself.

While maternal-fetal immunology diseases are rare, that doesn’t mean that the burden worldwide of rare diseases is not high. In general, it’s estimated that rare diseases affect more than 300 million people worldwide. Our goal is to address the gaps in clinical trials to bring forth an effective medicine to patients living with these rare maternal-fetal conditions.

Because HDFN can only be studied in pregnant people, what challenges come with developing a clinical trial for this understudied population? And are any challenges exacerbated because HDFN is also a rare disease and its patient population is small?

There are many challenges that can come with developing a clinical trial for pregnant individuals. First, there are challenges related to the inherent risks of the disease itself. Pregnancies affected by severe HDFN can cause significant fetal complications and mortality. We always need to keep these risks in mind throughout our research process.

Second, there is understandably fear around the unknown in any clinical trial, including concerns about the safety of the pregnant person and fetus. It’s important that we do everything in our power to design studies in ways that ensure participants feel informed and comfortable. We do this by coordinating meetings with our Patient Council, made up of individuals living with HDFN, to understand their challenges, including the mental, emotional, and socioeconomic impact of their disease journey. The Patient Council also allows us to gain first-hand perspectives on what potential participants’ reasons would be for enrolling in a clinical trial and what would present enrollment barriers, such as travel and time required, childcare, and questions around how the drug works. We address these barriers by ensuring we are thoughtful about the location of our site selections, the time required for our trial participants and that we are clearly communicating how our investigative medicine works and its potential impact on current medications. This helps us to create a patient-centered clinical trial experience.

Finally, when studying rare diseases like HDFN, the patient population by definition is small, and there are often specific criteria for entry, which can create a challenge in identifying patients for enrollment. However, setting specific criteria for inclusion or exclusion, such as gestational age, complications, or diagnoses experienced in prior pregnancies, co-morbidities like hypertension, and whether or not a person is pregnant with a single fetus or multiple, ensures we are providing the safest trial for the selected participants.

What advice would you give to those designing and executing clinical trials for pregnant populations?

We’ve learned some key lessons in the process of conducting the UNITY clinical program that can be applied not only to further development in HDFN and other rare maternal-fetal diseases but also to any future clinical trial that seeks to enroll pregnant people.

First, up-front time required to strategically plan execution should factor in greater stakeholder involvement and education than teams may be used to in traditional clinical development, which doesn’t typically involve two-patient participants (the pregnant individual and the developing fetus).

Second, a robust regulatory strategy and additional time for regulatory consultation with health authorities are key.

Third, investing in clinical trial awareness and education is essential in this population, for the pregnant person, family members, and caregivers, as well as their healthcare provider.

Finally, it’s also critical to ensure that the recruitment of clinical trial participants reflects the diverse backgrounds and experiences of patients. We do this by taking a close look at our clinical trial protocols to ensure we are eliminating barriers to access among diverse communities. We are thoughtful about our trial site selections, making sure that sites are open during hours in which participants can be available. Additionally, it is important that we continue to engage providers who can be very influential in driving diverse patient enrollment. Throughout the process, we are constantly building on what we have learned and incorporating these lessons into what we do next.

In addition to HDFN, UNITY’s nipocalimab is being studied in an additional nine indications. What are the challenges and benefits of such a large clinical trial program? And how is Janssen poised to overcome these challenges?

Nipocalimab is the only anti-FcRn currently being studied across three key autoantibody disease segments: maternal-fetal, rare autoantibody, and prevalent rheumatic diseases, and it addresses the specific mechanism believed to be the root cause of allo- and autoantibody diseases. We have prioritized 10 potential indications across these segments, driven by unmet need and actionable science.

The greatest benefit of studying a medicine in multiple indications in parallel is the potential opportunity to deliver a therapy to significantly more patients in a more compressed period of time versus if we studied the indications one by one.

As always, this can come with challenges around the size and complexity of the overall development program. Fortunately, we are building on Janssen’s deep experience and track record of developing treatments and studying multiple indications within a common immune pathway.  One example of this is TREMFYA (guselkumab), which was first approved in psoriasis and then psoriatic arthritis and is currently in Phase 3 pivotal studies running parallel in both Crohn's disease and ulcerative colitis — all interleukin (IL)-23-mediated diseases. The nipocalimab program has benefitted from the processes established and lessons learned in running multiple studies across different indications in the TREMFYA program, such as how to properly structure and resource the team and how to efficiently recruit patients across indications. I am not aware of any other company studying as many indications in parallel as we are with nipocalimab, but I also know that our proven experience coupled with our passion for patients living with auto- and alloantibody driven diseases positions us well to be able to execute this complex development program.

Over the next decade, what are you most looking forward to seeing in the rare disease space and the maternal-fetal space?

Looking ahead, I am excited to be part of an incredible team that is bringing hope to patients living with maternal-fetal diseases such as HDFN, as well as rare autoantibody diseases, including myasthenia gravis (MG), warm autoimmune hemolytic anemia (wAIHA), idiopathic inflammatory myopathies (IIM), chronic inflammatory demyelinating polyneuropathy (CIDP), and bullous pemphigoid (BP). Many of these diseases can cause mental and physical interruptions in a patient’s daily life, such as painful fluid-filled blisters on the skin for those living with BP and muscle weakness and fatigue for those living with MG. All of them impact a person’s ability to thrive and live life to the fullest. My ultimate hope is that by delivering new and groundbreaking therapies, we will enable patients and their families living with auto- and alloantibody diseases to reclaim their lives.

About The Expert:

Katie Abouzahr, MD, is VP, autoantibody (AAb) portfolio and maternal fetal disease area leader at Janssen Research and Development, LLC. In this role, Katie leads the development of assets in the AAb pathway portfolio and maternal fetal immunology disease area, of which includes Janssen’s lead investigative asset, nipocalimab, to address auto- and alloantibody driven diseases in multiple indications across maternal fetal, rare autoantibody, and prevalent rheumatology.

Katie joined Janssen in 2019 as a member of the Global Janssen R&D Strategy and Operations group and served as VP, compound development team leader for Janssen’s largest commercialized product, overseeing its development in multiple indications and its life cycle management strategy.

Katie 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 in London.

Follow Katie on LinkedIn here.