Revolutionizing Biologics (and Biology) through a Focus on Women

Revolutionizing Biologics (and Biology) through a Focus on Women

PAO-07-24-CL-03

Fab Biopharma was founded with a mission to address unmet needs in women’s health, focusing beyond reproductive health to conditions like Sjögren’s syndrome and lupus, which predominantly affect women and have historically been under-researched. Fab also prioritizes research that emphasizes female biology, utilizing female-derived cell lines and animal models to better understand disease mechanisms in women.  By leveraging bispecific receptors to target both T and B cells in autoimmune diseases and cutting-edge genetic and biomarker analysis, Fab aims to expedite development and reduce costs while creating effective treatments to address these unmet needs in women. In this Q&A, Chia Chia Sun and Gardiner Smith, two of Fab Biopharma’s founders, discuss the company’s vision and mission and the unique expertise the team brings to drive their novel approach, with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): Could you each tell me a little about your professional journeys and how they led to the founding of Fab Biopharma?

Gardiner Smith (GS): My journey began with studying chemistry at the undergraduate level, but I transitioned into intellectual property and business transactions within large pharmaceutical and biotech companies. At first, it didn’t occur to me to question the strategic directions of the companies I worked for; I assumed our shared goal was to help get new medicines into the hands of patients. However, a growing entrepreneurial drive led me to reconsider both the direction and purpose of these companies and my own. Through experiences in biological drug development and women’s health, I had seen the unrealized value of empowering women, particularly through better biologic drugs. Many women suffer from untreated diseases, and I realized that the dominant male perspective — including my own — might inherently limit the understanding and focus on female-centric conditions. This realization gave me a new purpose: dedicating more resources to address these unmet needs, which eventually led to the founding of Fab.

Chia Chia Sun (CCS): I traveled an academic path — I hold a master’s degree in genetics, specializing in cancer, an MBA with a focus on corporate finance, and a Master’s of Science in bioethics, which was dual-programmed with my genetics studies. After entering the industry, I mostly worked with large pharma companies, spending significant time in commercial market research and management consulting. The turning point came when I founded Damiva, a topical women’s health company. This venture, coupled with our biopharma experiences, expanded my awareness of the vast unmet needs in women’s health and my commitment to the field. About 12 years ago, both Gardiner and I decided to dedicate our careers to this cause. During the COVID-19 pandemic, Gardiner developed a business plan for a biologics firm focused on women’s health beyond reproductive issues, which was the genesis of Fab.

That decision turned out to be not only necessary but particularly timely, as the NIH (National Institutes of Health) just released a new grants policy focusing on women's health — the  first in its history — which aligns perfectly with our mission of pushing the boundaries of research through the lens of women’s health. The notice of special interest arises from Biden's executive order proposing $12 billion for new research in women's health.

Outside of reproductive health, the largest class of conditions that predominantly affect women are autoimmune diseases, so that became our focus. We prioritize diseases like Sjögren’s syndrome, because, despite its significant impact, there are currently no adequate therapeutic options, as well as lupus, due to both the need and our being the team that developed the first biologic lupus drug, Benlysta®.

DA: Why have drug development efforts not adequately addressed Sjögren’s syndrome?

CCS: Sjögren’s is a complex disease to diagnose because it often presents with nonspecific symptoms, such as dryness of mucous membranes, which can easily be confused with more common symptoms of menopause. Since women are typically diagnosed in their 40s and 50s, though the disease likely begins in their 20s and 30s, this results in a significant diagnosis bias. This delayed diagnosis means that there's a large portion of the patient population that remains unstudied and untreated, which has impeded the development of drugs against the disease.

DA: Once you had established that goal, how did you begin developing solutions?

CCS: As we began this work, I had the view that the industry already has plenty of technologies that could be redirected to address women’s diseases. We chose to pursue bispecific receptors, which are a new modality, but, like most inventions, they were built on earlier inventions — soluble single receptor fusion drugs and bispecific antibodies. We saw an opportunity to leverage those technologies and apply them uniquely to autoimmune diseases. In a similar manner, we decided that, rather than find novel drug targets, we would instead look at existing druggable targets where clinical data had already been generated and tackle them through this new approach. Finding smarter, more targeted applications of resources that have already been developed can really speed up development and reduce risks, which is especially critical for underrepresented diseases like Sjögren’s.

Another unique aspect of our mission is that our commitment to women extends beyond typical drug development; we are ensuring that our research and trials emphasize female biology, a factor that is too often overlooked in medical science. This involves prioritizing female animal models and incorporating female-derived cell lines in our disease-specific organoids. It’s about more than just meeting FDA requirements — it’s about redefining how we study and treat diseases that affect women, ensuring that our interventions are as relevant and effective as possible.

Many autoimmune diseases are primarily considered to be driven by T cells and later lead to B cell disease. Increasingly, we are realizing that autoimmune disease has both T and B cell components. Traditional approaches to drug development have focused on either targeting T cell disease to prevent B cell disease or to treat the B cell disease itself.

Sjögren’s involves both T and B cell components from the onset. The histopathology and genetics of Sjögren’s demonstrates an involvement of both types of cells very early — certainly by the time patients present with the disease — which suggests that targeting both cell types with the same drug could be more effective. Of the two best candidates currently in the clinic, one targets T cells and the other targets B cells. We believe that our approach leveraging bispecific technology will allow us to address both pathways in a single treatment, which we believe will enhance efficacy and has the potential for remission.

GS: Adding to that, our understanding of Sjögren’s and similar diseases like lupus, which we are also investigating, has evolved. Lupus is an incredibly heterogeneous disease, but we now know that, like Sjögren’s, it involves both T and B cells iteratively and early. Among many other accomplishments, our Chief Medical Officer, Bill Freimuth, M.D., developed the clinical endpoints for lupus that are still used today, which are based on a sophisticated organ domain analysis.  This methodology allows for detailed monitoring of disease impact on various organs, crucial for diseases as heterogenous as lupus and Sjögren’s. The variability in how the diseases present makes clinical trials particularly complex and challenging.

Our strategy using soluble bispecific receptors for both lupus and Sjögren’s aims to initiate therapy with this combined approach, potentially improving outcomes from the start, and has a lot of other advantages in terms of development speed, dosing, and pricing compared with establishing a combination therapy after approvals.

DA: For both of those diseases, do that heterogeneity, the delayed diagnosis, and other factors create challenges in clinical trials?

CCS: Clinical trials for diseases like Sjögren’s and lupus are notoriously challenging due to their heterogeneity. Bill’s work has been instrumental in defining clinical endpoints that reflect the multi-organ impact of these diseases. For Sjögren’s, adapting these rigorous criteria ensures that our trials are comprehensive and that our treatments address the disease effectively across various organ systems.

GS: Our strategy incorporates cutting-edge genetic and biomarker analysis to enhance the predictability of our phase II trials. By identifying and utilizing robust markers, we aim to better forecast the outcomes of pivotal phase III trials, which is crucial for efficiently directing our resources and efforts.

We have the key expertise in house, but we're also collaborating with some of the leading rheumatologists in the country, who have many Sjögren’s and lupus patients and can not only provide us with access to critical patient samples but also deep insights into the biomarkers associated with these diseases. Our intellectual property around specific B cell biomarkers, used in conjunction with our bispecific receptors, positions us to pioneer effective therapies for Sjögren’s and lupus.

DA: Since you’re targeting both B and T cells simultaneously for both Sjögren’s and lupus, is it feasible that the same candidate bispecific receptor could treat both diseases?

GS: We've decided to use different receptor pair combinations for lupus and Sjögren’s for both risk reduction and commercial reasons. Additionally, we're exploring separate therapeutic areas, like osteoimmunology and asthma, both of which disproportionately affect women compared with men. Our diverse approach allows us to minimize risk if a particular molecule shows a liability and to optimize both scientific and marketing strategies for different molecules. Our team, including the fourth founder, Reiner Gentz, who has authored many of the foundational  TNF family publications, focuses on diverse applications of our technologies, and it was his idea to develop bispecific receptors rather than bispecific antibodies, which was the original plan.

CCS: The name Fab was originally meant to stand for “female antibody,” but with that pivot it became “female autoimmune biologic,” which is more expansive.

GS: With antibodies, there are so many possibilities: traditional drug discovery methods like phage display or the use of transgenic mice generate millions of novel binding regions to screen and find your candidate. Soluble receptors are a different story. They’ve already evolved to bind a specific ligand. So, rather than starting with millions of combinations, we have one or two dozen to investigate. We can then generate diverse candidates by combining each B cell receptor with each T cell receptor.  This focused diversity means we're not overwhelmed by volume and can rapidly screen and select the most promising candidates. This streamlined process allows us to advance from initial selection to lead compounds in just three to six months, which is very different from antibody discovery.

CCS: Although soluble receptors are relatively unexplored, Fab isn’t alone in seeing the value of soluble receptors for autoimmune diseases.  Vertex Pharmaceuticals recently acquired Alpine Immune Sciences for just shy of $5 billion, largely on the strength of Alpine’s lead asset, povetacicept, which is a soluble TACI receptor that’s a dual BAFF and APRIL antagonist. It’s currently in phase II trials for a small indication — IGA nephropathy — but they claim that it shows Humira-like universal properties. Alpine's approach with povetacicept, specifically how they optimized the receptor for BAFF but not APRIL to avoid side effects, mirrors our strategy to not overly optimize receptors for the same reason. And povetacicept is a single receptor, not a bispecific like what we are developing.

DA: How generalizable do you view the strategy of simultaneously targeting B and T cells across autoimmune diseases and beyond?

CCS: The approach is highly generalizable. B and T cell activities are commonly linked, so managing both within a safe and effective therapeutic window is crucial. For now, our priority is diseases like Sjögren’s and lupus, which significantly affect glandular and organ systems, but we’re also exploring conditions like osteoimmunology and asthma, which may not traditionally be seen as autoimmune but have strong immunological components.

GS: It’s a nuanced approach. For instance, osteoporosis is often considered a metabolic condition rather than strictly autoimmune. Yet, there's a clear immunological aspect to it. Similarly, while asthma is generally viewed as a pediatric condition, it is significantly more severe in women than in men, illustrating the gender-specific differences in disease manifestation and severity.

CCS: Because our soluble receptors bind extracellular cytokines and ligands and effector molecules rather than membrane-bound ones, they should be safer in autoimmune disease. That means that we can develop drugs for indications like asthma and osteoporosis where you need a robust safety profile because we are trying to only target one organ system: the lungs for asthma and bone for osteoporosis.

GS: When you bind cell membranes with bispecific drugs, there is the possibility that it results in bringing two cell types together, which can have consequences. By focusing on extracellular targets, we can fine-tune our approach to 'gobble up' excess harmful molecules without disrupting cell integrity.

DA: With that generalizability in mind, what is your current strategy for how to handle the multitude of therapeutic possibilities that this work presents?

GS: With Sjögren’s and lupus, we can conduct parallel development efficiently, because the screening assays, the organoid models for kidney and salivary glands, and so on overlap for the two diseases. That lets us pursue both programs and reduce costs significantly. For example, the animal model used for lupus, which was validated by our team during the development of Benlysta, is also applicable to Sjögren’s. This synergy enables us to push these programs forward swiftly, maintaining most activities in-house up to phase IIA or even into pivotal studies.

CCS: For conditions where the path to approval is less established, like Sjögren’s, or for diseases with rapid model readouts, like osteoporosis, our approach might be different.

GS: Osteoporosis is a good candidate for out-licensing, letting us focus resources on areas where we can make the most impact quickly. Similarly, for conditions like scleroderma and asthma, where there is already a substantial safety database, out-licensing becomes a practical option. Our approach is flexible; we're prepared to out-license where it strategically makes sense to accelerate development and leverage external expertise.

Our immediate priority remains to advance our lead programs for lupus and Sjögren’s through to clinical stages. These programs form the backbone of our development strategy, but we remain agile, ready to pivot and adapt strategies for other indications based on emerging data and partnership opportunities.

DA: Can you tell us a bit more about your investment and funding strategy, particularly in the near term?

GS: Our progress to date in data accumulation, intellectual property, and operational planning has largely been powered by the initial investments from our four cofounders. This foundational funding has allowed us to establish a robust platform on which we can build further.

We have an important partnership with Wheeler Bio, a boutique CDMO with co-investment in the potential of our biologics. They contribute services and expertise in their facilities, which helps us manage costs and risks effectively. As we move forward, we plan to continue this partnership into the scale-up phase of our projects.

DA: You mentioned earlier that the company is not only focusing on diseases that affect women; you are also looking to rethink drug science from a female perspective.  Can you expand on what that will mean?

CCS: A change in perspective is essential across the entire pharma landscape. For example, while the gender gap in clinical trial recruitment has narrowed significantly in the last decade, there remains a critical need for further inclusivity.

One major point of differentiation is our focus on autoimmune diseases that disproportionately affect women. We prioritize diseases based on their prevalence among women compared with men. Moreover, our drug development process overall is driven from a female perspective and intensely focused on the female biology; we predominantly use female animal models to better understand disease mechanisms in women. 

GS: While it’s common to acknowledge sexual dimorphism in mammals, it's rare to see it significantly influence pharmaceutical research. Our emphasis on these differences is not just academic; it's practical and necessary for developing effective treatments.

CCS: We are finally getting some real insight into why autoimmune diseases in general are more prevalent in women than men. Some very recent work has indicated that the Xist complex — which is involved in X chromosome inactivation in women — may be directly involved in the development of autoimmune diseases.

Those results also point to some of the challenges in translating results from animal models to clinical trials. We know that, in female mice, somewhere between 3% and 7% of genes on the inactivated X chromosome are partially expressed, but in humans it’s more like 20–30%. Our models must adapt to reflect these differences accurately.

We are paying very close attention to the epidemiology of these autoimmune diseases. It’s not only gender: for example, Sjögren’s manifests very differently in Asians than in Caucasians, and Hispanics of both genders are overrepresented for lupus. By focusing on these biological nuances, we not only address gaps in current treatment options but also pave the way for more personalized and effective therapies. This approach isn't just about being thorough; it's about being right and making a meaningful impact where it's most needed.

GS: Our goal is to achieve a balanced representation of women and men in our management and board. Once we secure additional funding, we'll be better positioned to recruit and achieve this balance.

CCS: It's about getting the balance right. This diversity encompasses mental, intellectual, emotional, communicative, observational, and data processing differences that are critical for innovatively addressing women's health issues.

GS: This is vital because if we lack diverse perspectives, especially at the senior level, our approach to developing biologics for women’s diseases won’t be as effective. It’s about what we don’t know, and without a diverse team, we miss out on insights that could lead to breakthroughs.

CCS: To that end, we're dedicating substantial research on drug science from the female perspective, including understanding more about mechanisms like Xist. The increasing body of literature supports this approach, and it's exciting to see the field evolve.

When I speak on panels, I make it clear: we are not just another biotech company. We are actively developing and testing treatments specifically designed for women, and this mission is crucial. It's about making our presence known and our voices heard in a space where such perspectives are often sidelined. And while our approach is innovative, it still adheres to established scientific and business protocols. We're leveraging what's known and proven, like the models used in developing Benlysta, and applying it to our work without reinventing the wheel every step of the way.

GS: It reminds me of a quote from Benjamin Franklin: "We get old too soon and wise too late." In our case, we're combining the youthful energy and passion of our team with a seasoned understanding of female biologics development. This combination is rare and key to our success.

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