From The Editor | April 25, 2022

Is Janssen's Pathway Approach The Future Of Drug Development?

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

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Terence Rooney, M.D., is a rheumatologist who is excited about the future of drug development. He has seen huge advancements made in medicine over the last 20 years and notes one of the most significant was the move from evidence-based medicine to targeted therapies.

"Twenty years ago, when I was a junior rheumatologist, medicines were engineered to block specific molecules and pathways because we understood that was important to controlling specific diseases," says Rooney, VP of clinical development - immunology at Janssen. "At that time, the first wave of those medicines to come into the immune-mediated inflammatory disease space was those that block tumor necrosis factor (TNF). It transformed care in my specialty area of rheumatology and cleared a lot of the wheelchairs and crutches out of waiting rooms."

Since then, Rooney notes that the industry has seen a transformation in many of the more common inflammatory diseases such as rheumatoid arthritis, psoriasis, and digestive disorders, which impact around 30 million patients. Despite that success, during what he calls the golden age for therapeutics and immune-mediated inflammatory disease, fewer than 10% of patients reached the goal of remission.

"There is still tremendous opportunity going forward, and Janssen has focused on broadening the aperture from focusing on big diseases to looking at more underserved areas," notes Rooney. "That approach has been driven by what we call a pathway approach to developing new medicines. Rather than focus on specific diseases, the new approach attempts to match the biology of a pathway to unmet medical need for patients, across a broad range of immune-mediated, inflammatory disease. That will lead us forward in the coming years."

Newman Yeilding, M.D., head of immunology development at Janssen, agrees. He states that the last 20 years have provided the company with insights that are evolving how it thinks about disease. The company has learned that the molecular underpinnings of disease offer a new way of classifying disease. Janssen now has more of a molecular or taxonomic way of looking at disease and the molecular pathways that are dysfunctional, especially in immune-mediated diseases that cut across many different organ systems.

“Those learnings are driving our thinking about how we evolve the future development of drugs and understanding the molecular underpinnings of various diseases in addition to the organ systems that they impact,” he says. “We are in the process of evolving how we think about disease.”

CHALLENGES TO OVERCOME

There were multiple challenges that had to be overcome for this development model to come to fruition. Some of those challenges revolved around the technology needed to better understand the molecular basis of disease. For example, an upregulated immune pathway is not necessarily harmful. Yeilding cites congestive heart failure as one example where TNF-α is upregulated, but the blockade of TNF in patients with heart failure did not improve disease, and instead increased the risk of mortality. “Observations like this continue to challenge us in our true understanding of diseases.”

The company also learned that diseases are oftentimes not driven by a single pathway. That makes drug development for those diseases more difficult, as researchers must identify how to address the dysregulated pathways that drive a disease.

“Those are challenges that we still need to overcome in immune-mediated inflammatory disease,” says Rooney. “Multiple pathways can play a role in driving diseases in humans. Precision medicine is also an issue we’re focused on. There are multiple therapies available to patients of some of the more prevalent diseases. How do you decide which one is going to be the right treatment for a given patient at a given time? To get some patients into remission, they may need a targeted combination therapy.”

Over the last two decades, the field, the industry, and medical science have not solved those issues in immunology the way they have in oncology. There are companion diagnostic tests that will tell researchers, up front, what medicine might be right for a patient’s specific cancer. There are also examples of successful combinations of these advanced or targeted therapies in oncology. Unfortunately, the industry has not advanced to that stage with immune-mediated inflammatory disease, an avenue that will need to be addressed in the future.

THE PATHWAY APPROACH

Most of the progress made in recent years has been around big diseases such as Dercum’s disease and those of the gastrointestinal tract. Although some of those diseases now have multiple targeted therapies, the field of medicine generally only gets one in 10 patients into a state of sustained remission. There are many other underserved diseases that have no approved treatments available, and where even the off-label use of medicines is not particularly effective.

Those pain points provoked Janssen Immunology to take a new look at its strategy of understanding disease biology. The company’s pathway approach was born out of a need to address both issues.

“A decade ago, we were a disease-focused company,” says Yeilding. “We focused on three key immunology diseases – psoriasis, inflammatory bowel disease, and rheumatoid arthritis. Through that focus, we developed deep insights into the pathways that are involved in those diseases, but also recognized that those pathways were involved in multiple other diseases. We have evolved to a balanced approach leveraging the insights gained as a disease-focused company but also embracing the opportunity afforded by a pathway approach to address multiple diseases with a single medicine.”

A COMPLEMENTARY APPROACH

Yeilding notes the goal 20 years ago was simply making patients feel better. As new medicines and insights emerge, the goal is being elevated. Researchers are no longer happy to treat diseases. The new goal is disease remission. “While it’s good to feel better, it’s better to feel good,” said Rooney.

“We have invested heavily in understanding the molecular underpinnings of disease via our translational science group,” says Rooney. “In clinical trials, we’re getting tissue biopsies, blood samples, and other samples that can help us understand disease pathogenesis and how our medicines affect them. This also helps us gain insights into how other pathways might influence disease biology. Insights are also gained from the external environment.”

Rooney notes there is no way the company could gain these insights working in isolation. Therefore, Janssen has a long-standing commitment to external collaboration through partnerships with academia and support of external innovation and entrepreneurs. For instance, together with Johnson & Johnson Innovation, they have just launched the “Immunology Innovations QuickFire Challenge: Precision Medicine in Immune-Mediated Disease,” a scientific crowdsourcing initiative seeking innovators with transformative potential solutions to advance precision medicine approached in autoimmune disease. The challenge invites entrepreneurs and scientists for the chance to apply for up to $500,000 in funding, access to the global network of JLABs, and expert mentorship.

In its emphasis on collaboration with the external medical and scientific environments, Janssen hopes to understand these pathways and their relevance for disease, disease pathophysiology in different tissues and organs, and the biomarkers for mechanistic stratification. Rooney, Yeilding, and colleagues believe these insights will lead to precision approaches, enabling them to develop new medicines with mechanisms of action tailored to differentiated patient populations.

“We believe that precision medicine will complement our pathway approach,” he adds. “Precision medicine is about getting the right drug to the right patient at the right time. But that approach may only work for certain heterogeneous diseases where patient subpopulations can be segregated according to which specific pathway drives their disease. Other diseases whose biology is driven not by one pathway, but instead by multiple pathways, may require combination therapy approaches that target those multiple underlying pathways.”

As an example of precision medicine, Rooney points to breast cancer. A biopsy of a person’s breast tumor will show whether it has a particular biologic marker that makes it a good candidate for a treatment that targets the biomarker. The use of biomarkers has been successful in transforming healthcare for cancer patients. Unfortunately, there are very few such biomarkers in the world of immune-mediated inflammatory disease.

In fact, genetic association studies, functional studies, and clinical observations suggest that there is substantial overlap among immune-mediated inflammatory disorders affecting different organ systems, but the cellular mechanisms are largely unknown. Janssen is hoping to change that and advance the understanding of pathway biology through another external effort and strategic collaboration with Oxford University to create a cellular map of the genes and proteins implicated across a range of immune-mediated inflammatory disorders to characterize pharmacologically relevant therapeutic targets.

“It’s much more typical to have shades of gray,” says Rooney. “We have a medicine targeting a pathway or a molecule, and that molecule is overexpressed in everyone with the disease. Still, the molecule might be more expressed in some than others. We will set the thresholds of which people have just enough or more of the molecule to lead us to believe they would benefit from the medicine.”

“Our understanding of immune disorders is expanding at an extraordinary rate,” adds Yeilding. “The immune system is complex. Much of our understanding has come from evaluating biology at a tissue level, for example, evaluating the expression of different genes in tissues. We’re seeing technologies evolve to enable evaluation of what happens at a more cellular level. The tools we now have available to deconvolute what’s happening in the tissue at a cellular level have evolved over the last 20 years. We hope that this will provide us the opportunity to understand what drives a patient’s disease and gain the same insights into immunology that drug developers have had in oncology.”

THE IMPACT ON CLINICAL TRIALS

This new approach to drug development has impacted how Janssen conducts clinical trials from early development all the way through to late development. A big focus of its clinical programs now starts with understanding how a medicine will impact a pathway and the disease it is targeting.

“We start with a hypothesis of which patients we think the medicine will be most suitable for,” says Yeilding. “We determine that by identifying a subset of patients where the pathway is dysregulated. As we start our trials, we’re trying to figure out which patients are going to benefit from our medicine. We then try to weed out those patients where the benefit/risk ratio is not going to be favorable.”

Today, companies are looking for ways to accelerate clinical programs and be more efficient. By enriching the patient population to ensure the treatment effect of a drug will be large, a sponsor company can perform smaller trials and streamline its development programs.

“Certain diseases that are primarily driven by a single pathway do not require an enrichment strategy,” states Yeilding. “For example, a key pathway has been shown to drive the biology of psoriasis so that with the more effective therapies available today, as few as 20 patients are required to convincingly discern the treatment effect of a drug. Most patients will respond robustly and completely clear their skin. For other more heterogeneous diseases, we will need to identify the biomarkers that will enable us to enrich for patient populations where our drugs are highly effective, and that can ultimately lead to smaller and quicker studies as well as easier discussions with regulatory agencies as to the benefit/risk ratio of a treatment.”

THE FUTURE OF DRUG DISCOVERY

Going forward, will other drug developers adopt a similar approach? Rooney thinks the short answer is yes, and the oncology field has led the way.

“We have a longer-term vision in that direction for immune- mediated disease,” he notes. “We want to get to the point where we can convince ourselves, patients, and regulatory authorities that diseases can be classified according to molecular or pathway taxonomy and that a medicine targeting the dysregulated pathway will help patients with that molecular disease. That’s currently a high bar, but it’s definitely part of our vision for the future. We have gained insights on the breadth of diseases that are impacted by critical immune pathways. That has given us knowledge on how we can address the unmet needs that exist in immune-mediated diseases. As we develop new drugs, we’re already starting to think about how we can address those unmet needs more rapidly. That will involve developing our assets for multiple diseases rather than one disease at a time.”

“Understanding the molecular pathogenesis of one disease may give us insights into a whole group of diseases that may be impacted by our medicines,” adds Yeilding.

“There’s a prevailing view that things are tough in certain diseases for drug developers, especially disorders that already have multiple approved therapies. That means the bar is high for new treatments. Where do we go from here? Our view is that we are on the verge of another golden age. We believe we can raise the bar for diseases that have treatments and forge into areas that are highly underserved.”

As the immunology group at Janssen invests in the rare disease space, it is doing so in partnership with other therapeutic areas within the company. Rooney states that the immunology therapeutic area has potential to partner, for example, with colleagues in the neuroscience, oncology, and cardiovascular groups. It all depends on where the biology and unmet needs intersect.

Newman Yeilding and Terence Rooney

TERENCE ROONEY, M.D., VP of Clinical Development – Immunology Janssen

NEWMAN YEILDING, M.D., Head Of Immunology Development Janssen