Science Forward

Every research and development organization has its own approach to scientific discovery. For Horizon, that R&D approach is all about pathways — especially the premier pathways that lead to a variety of diseases.

Whereas a conventional pathway is a series of molecules that interact to carry out a specific biological process, a premier pathway has a central role involved in aggregating the many biological inputs that lead to disease and underlie the transition from an early disease state to a more severe condition. For this reason, scientists at Horizon keep premier pathways at the center of their R&D strategy, which has value both for research and patients.

Following Pathways in the Lab

Homing in on premier pathways can uncover biological processes directly related to disease development. However, this type of research requires diligence, which may mean looking across subsets of a disease or a patient population to arrive at a central underlying biological mechanism.

“A good example is our approach to Thyroid Eye Disease (TED),” said Bill Rees, Ph.D., vice president, translational sciences. “There is a chronic version without inflammation and an acute version that has lots of inflammation. Only focusing on acute disease presents the challenge of sorting through inflammatory processes, which can have infinite possibilities. But if you look across all TED, the dysregulation of a central underlying pathway is revealed.”

Human cells use many molecular pathways to do their jobs, and dysfunction in any one of these could lead to disease. Because dysfunction in one pathway can be common across multiple diseases, the components of a single premier pathway can be potential therapeutic targets for more than one condition.

“Using a pathway approach means we understand the fundamental biology so well that we can apply a therapeutic across different disease states where the pathway is operant, which we are doing across our pipeline,” said Robert Stoffel, Ph.D., vice president, research.

Pathways to Address Unmet Need for Patients

Thinking about R&D through a pathways lens reflects Horizon’s patient-first approach. For example, Horizon researchers identified the centrality of a key pathway in a number of autoimmune and inflammatory diseases. Not only did these teams take a new approach to designing a molecule to block the pathway, but they also analyzed dosing in preclinical models to limit the amount of medicine someone takes.

“We use our knowledge of fundamental disease pathways to help us think about scientific challenges in new ways or advance a clinical path that others thought was insurmountable,” said Theresa Podrebarac, M.D., M.Sc., senior vice president, clinical development. “It’s not just about choosing a pathway – it’s about having insights to help us make calculated choices that will benefit patients.”

"There’s a back-and-forth involved," Stoffel added. "A pathways approach can help arrive at new treatments, but a patient’s response helps fine-tune those therapies."

“We’re able to use the knowledge we acquire from clinical trials to understand who responds to a therapy and who doesn’t,” he said. “Then we can use this information to make more informed decisions during early R&D.”

Measuring a wide range of patient-reported outcomes plays an important role, not only in understanding how a therapy affects each patient during clinical trials but also in monitoring how it works for patients once it’s on the market — and how next iterations of the therapy could be made even better from their feedback.

A deep understanding of pathways also helps determine where investments will be most valuable.

“Despite the fact we are a small company, we are willing to interrogate many disease areas, even though this might limit the ability to invest in one indication deeply,” Podrebarac said. “But we understand many patient populations can’t afford to wait any longer, so we use our pathway-centric approach to make biologically informed decisions when we take calculated risks to move our pipeline forward.”

Pathway-Centric Into the Future

The pathways approach positions Horizon’s R&D well for the coming years, especially as new technologies emerge.

“We used to grind up tissue to investigate it, but this meant we couldn’t study molecular processes within their biological context,” Rees said. “Now, technology has evolved such that we can take a slice and simultaneously investigate hundreds of genes and proteins within the context of tissue, helping us understand their intrinsic role. As this kind of work increases, so too will our odds of finding more premier pathways to go after.”

To further drive the pathways approach to drug development, partnerships have been and will continue to be vitally important.

“At Horizon, we are highly collaborative, both within our walls and with external partners,” Rees said. “As an industry, we need to continue moving beyond isolated experiments in individual labs, because R&D fundamentally benefits from diversity of thought.”

That said, for areas such as rare, autoimmune and severe inflammatory diseases, which are central to Horizon’s mission, sometimes charting a new path is critical.

“My philosophy has been if the herd is going in a certain direction, what might they be missing by not looking elsewhere?” Podrebarac said. “At Horizon, we are trying to carve a path into territories where the herd is not going and where there’s additional opportunity. In this way, we hope to make the most impact for patients in need.”

Any strategy, even one with a strong track record, comes with challenges. For premier pathways, it’s often narrowing down the near-endless possibilities within cells to arrive at a single promising pathway to focus on.

As Rees noted, “It requires persistence to find what you are looking for, given so many biological processes are disrupted in disease. Keeping ‘premier’ pathways as our North Star helps us make decisions based on both disease biology and patient need.”

Our team is thinking differently about halting disease activity that leads to inflammation through CD40 ligand. Found on the surface of T cells, CD40 ligand is part of a key co-stimulatory pathway that plays a crucial role in driving immune responses. When external invaders enter the body, this pathway is required to form germinal centers, structures which act as a defense system by producing antibodies.

In certain autoimmune diseases, overactivation of this pathway occurs when CD40 ligand is turned on via its interaction with CD40 receptor, found on B cells as well as a variety of other tissues. As a result, the immune system overproduces antibodies and mistakenly attacks the body, leading to the inflammation that is seen in many autoimmune diseases such as Sjögren’s syndrome, rheumatoid arthritis and a variety of immune mediated kidney diseases.

Horizon’s R&D team took a science forward approach to solve this problem and generated dazodalibep, a fusion protein that blocks CD40 ligand’s interaction with CD40. Dazodalibep is thought to disrupt over-activation of this key pathway, resulting in shrinkage of germinal centers and reduction in auto-antibody levels. As a fusion protein, dazodalibep is structurally different from the antibody-based approaches previously used to target this pathway. With this unique approach, Horizon hopes to suppress disease activity for people living with a variety of autoimmune diseases.