Magazine Article | December 29, 2016

Janssen Immunology — Science & Market Drivers

Source: Life Science Leader

By Wayne Koberstein, Executive Editor, Life Science Leader magazine
Follow Me On Twitter @WayneKoberstein

From discovery through development, commercial savviness teams up with scientific progress in this J&J business unit.

The name Janssen lives on in the pharmaceutical organizations of Johnson & Johnson, carrying the meaning its founder, Dr. Paul Janssen, gave it through his namesake company’s achievements: bold but logical innovation that sometimes goes beyond serving markets to creating them. He taught that vast new markets can emerge in response to products that are the first to address a commonly accepted condition. Yet the contemporary Janssen biopharma entities don’t just replicate the DNA of drug discovery and development inherited from Dr. Janssen; they have gone on to explore all emerging pathways to new therapies for a widening variety of disease areas. One of the best examples of the expansion in approaches and areas is Janssen Immunology.

Sue Dillon, Ph.D., who heads the company’s global therapeutic area of immunology, updates us on how Janssen Immunology has changed strategically since she last spoke with us for our story on Janssen Biotech in March 2012. She especially focuses on how the company and the immunology group use market insights to guide strategy, therapeutic focus, and product development. In doing so, she also describes Janssen’s main mechanism for marrying the precommercial and commercial functions — its unique, multi-unit structure.

“Our organization drives end-to-end drug discovery through late-stage development and integrates the R&D and commercial groups to achieve short-term project execution, as well as longer-term strategic planning,” Dillon says.

Structure Power
Immunology is one of five therapeutic areas (TAs) in the Janssen Research & Development organization, along with cardiovascular & metabolism, infectious disease & vaccines, neuroscience, and oncology. The TAs work together with functional units — such as Janssen Biotherapeutics (large molecule expertise), Discovery Sciences (small molecule expertise), Global Regulatory Affairs, and Global Clinical Operations — to execute discovery and development projects. As Dillon observes, immunology is a key growth driver for the company globally, with almost $6 billion in annual sales mostly from four products — Remicade (infliximab), approved for treating Crohn’s disease and a host of other inflammatory conditions; Simponi (golimumab), for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis; Simponi Aria (golimumab for infusion) for rheumatoid arthritis; and Stelara (ustekinumab), for psoriasis, psoriatic arthritis, and Crohn’s disease. She says immunology is also a chief driver of growth in value “from the pipeline and scientific innovation perspectives.”

One significant new addition inside Janssen and the Immunology organization is its Disease Area Strongholds (DASs), groups of Janssen experts in “priority diseases”: inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis. Each of the other four therapeutic area units has its own set of DASs, based on common criteria. Dillon explains, “A DAS is chartered based on unmet need, compelling science, commercial potential, and where we have achieved or look to achieve the capabilities and pipeline that will deliver transformational medical innovations for patients and leadership for Janssen.”

Each DAS consists of an R&D leader, a global commercial coleader, and “a core team of disease area R&D experts in discovery, translational medicine, and development,” she says. “The DAS leaders work closely with our discovery and development groups and with the Johnson & Johnson Innovation Centers to scout and access compelling external science and innovations that align with the DAS strategy.”

It would take a wall chart to illustrate the entire variety of legal and operational entities now bearing the Janssen name, from Janssen Biotech, the commercial arm of Immunology and Oncology in the United States, to Dr. Paul’s heritage company Janssen Pharmaceutica in Belgium. But the therapeutic area units are all global, as are many of the functions that support them, including Janssen Global Services, which contains the Global Commercial Strategy Organization and Communication & Public Affairs.

In recent years, says Dillon, the company has augmented its internal forces with external relationships by creating and building the Johnson & Johnson Innovation group, now with Innovation Centers (ICs) in California, Boston, London, and Asia Pacific, and JLABS incubators in San Diego, San Francisco, Houston, Toronto, and Cambridge, MA. “The ICs are designed to access scientific innovation, working with biotechs and academic leaders, to bring in cutting-edge scientific projects at the discovery and early development stage that are aligned with our scientific strategies,” she says. “We typically work collaboratively with partners and retain an option to bring the assets into our portfolio at defined milestones.”

The company has added several innovation incubators in recent years: the Janssen Microbiome Institute, led by Dirk Gevers, former group leader at the Broad Institute and researcher on the Human Microbiome Project; the Disease Interception Accelerator, led by Ben Wiegand, a veteran J&J executive; and Janssen Immunosciences, led by Murray McKinnon, another J&J veteran, which is “advancing new immunology concepts with broad therapeutic potential.” The groups interact with the TAs and J&J ICs to leverage their capabilities.

Therapeutic Progression
In immunology, a therapeutic area that has chiefly concerned inflammatory and autoimmune diseases, the existing treatments have transformed patients’ lives but tied them to a lifetime of drug maintenance. Of course, as with any chronic therapy, drug resistance can grow, and side effects may worsen over time. Thus, the next generation of immunology medicines must meet a higher standard, not just improving on current agents but surpassing them with a limited course of treatment that brings the disease to a halt.

“We are focused on bringing transformational innovations to patients with RA, IBD, and psoriasis where we believe there is still a huge unmet need, even with the medicines we and others have delivered in recent years,” Dillon says. “RA and IBD patients rarely achieve full remission, so we are focused on new mechanisms of action that we believe can induce immunologic tolerance, restore homeostasis to the immune system, and/ or eliminate pathogenic autoimmune cells in patients with established disease. At the same time, we’re building the capabilities to identify and treat these diseases much earlier to intercept or even prevent the destructive disease processes.”

All current treatments for such conditions suppress key proteins in the pro-inflammatory pathways, including TNF (tumor necrosis factor), JAK (janus kinase), IL-23, IL-17, and various cytokines, mainly to moderate symptoms. But as science produces more and more knowledge about the root causes of those diseases, hope grows for something more like a cure. “Better understanding of genetic susceptibilities and environmental factors including the host microbiome is setting us up for defining the antigenic triggers of autoimmune disease, which could translate into therapeutics that can target the auto-reactive cells that escape from the normal mechanisms that keep those cells inactive,” says Dillon. The same knowledge would make it possible to identify patients earlier in the disease cycle, treat them sooner, and potentially induce long-term remissions and cures, in her view.

“That is where the science is leading us. Because of the breakthroughs in genomics and the emergence of various platforms that allow us to sequence and understand the T-cell receptor repertoire, we can learn exactly what antigens are recognized by T cells in people with autoimmune disease and how autoreactive clones differ in populations at different time points in the disease, and so on,” she says.

“We typically work collaboratively with partners and retain an option to bring the assets into our portfolio at defined milestones.”

Janssen is working on “shifting the paradigm” from blocking inflammation to not only interrupting the disease triggers but also reestablishing “immune homeostasis,” according to Dillon. “We want to restore the normal constituents and mechanisms that should be there as part of normal immunosurveillance in order to block autoimmune responses.”

In the near term, however, research will still concentrate on creating “better and better cytokine blockade,” she says. She cites the example of advanced therapeutics for psoriasis, which began with Enbrel (etanercept), moved to Humira (adalimumab), then to Stelara (ustekinumab). “As we showed in a head-to-head study years ago, Stelara is superior to Enbrel. Now with the IL-17 and IL-23 blockers, both clearly are the most potent mechanisms out there.”

Janssen recently presented findings from a Phase 3 trial with its IL-23 specific antibody drug candidate, guselkumab, in patients with moderate to severe plaque psoriasis, and showed the superiority of guselkumab over Humira. Additional data from a large Phase 3 development program, which includes a second trial comparing guselkumab with Humira and a third looking at patients who have an inadequate response to Stelara and are treated with guselkumab, are forthcoming. Guselkumab has been submitted to the FDA and EMA for approval. Dillon makes the point that the very design of the trial shows how much higher the bar has risen as newer drugs have entered the market. Janssen is also pursuing other indications for its newer therapeutics. As with Stelara, which has now been approved for Crohn’s disease in the United States and European Union, the company is eyeing plans for guselkumab in Crohn’s disease and other lifecyle indications such as psoriatic arthritis.

“None of the existing drugs for Crohn’s, RA, or IBD interrupts the process,” she says. “They dampen inflammation and achieve remarkable effects in symptoms and remission in some cases. But in general, if you stop the drug, the disease remains, and, particularly in RA and IBD, many patients who initially have very good response lose their response for a variety of reasons, and there has been a large surge in TNF-inadequate responders in Crohn’s disease, for example. Therefore, we believe Stelara will have a large impact in such cases.”

In addition to RA, IBD, and psoriasis, the group has launched early efforts with Stelara and Simponi in other autoimmune diseases, including Lupus and Type I Diabetes (T1D), looking at how they may restore tolerance in the immune system. In a collaboration with the Lupus Research Alliance, it is evaluating Stelara in a Phase 2 study, and it recently launched a proofof- concept study with Simponi in patients with newly diagnosed T1D.

Immunology is also exploring the potential role of the microbiome as a predictor of inflammatory and autoimmune disease, aiming to develop related therapeutics and diagnostics. In establishing the Janssen Human Microbiome Institute and the Disease Interception Accelerator, the company is greatly expanding its therapeutic targets and approaches, according to Dillon. Some of the new targets are T1D, gestational diabetes, COPD, perinatal depression, presbyopia and cataracts, and oropharyngeal/cervical cancer.

“These are not traditional drug discovery or development efforts,” she says. “These incubators are looking at the diseases in a very different way. They have selected the diseases very carefully, based on the latest knowledge of risk factors and access to patients at high risk of developing certain diseases, and they will be figuring out approaches we can use to intervene.” Unlike the incubators serving the entire Janssen group, Janssen Immunosciences is a dedicated part of Dillon’s team but is focused more on immunology science, looking for platforms that could be applicable in many different diseases, even outside of the autoimmune area.

So, by this time, you’re wondering how the commercial input enters this picture of disease and therapeutic mechanisms. Well, the first common denominator of mechanisms in development and markets in motion is the future. Janssen Immunology is not poring over new treatment modes just for its amusement; its scientific aims are directly tied to the practice settings, treatment paradigms, and cost structures of real-world healthcare systems in which its products will compete — otherwise known as “the market.” Perhaps the potential benefits for those systems should be obvious, but in fact they must be proven, expressed, and communicated to the market players, from patients to physicians to payers. What is the “value proposition” of stepping beyond treating symptoms to halting disease?

Commercial Integration
In healthcare, market needs and medical needs are not identical, but they are closely related. If a company can introduce products that, say, liberate patients from chronic disease and payers from the related costs, of course it has a potential competitive advantage. But to accomplish such a feat takes effective communication in two directions — from the market to the science and from the science to the market. Janssen Immunology relies on a key ally in the company, the Global Commercial Strategy Organization (GCSO), to ensure that communication.

As Dillon explains, the GCSO furnishes expertise in strategic analytics, market research, market dynamics, modeling, commercialization, strategic marketing, market access, medical affairs, and other related intelligence to establish the strongest possible product profiles for treatments in its current portfolio, as well as therapeutics advancing through the pipeline. “Our unique DAS model promotes close collaboration between the GCSO aligned to disease areas working strategically with their R&D counterparts. This ensures that insights from KOLs and experts in the field gathered by the GCSO team are communicated to scientists in the lab to bring about the next wave of transformations for patients,” says Dillon.

Each DAS team has both an R&D leader and a global commercial strategy leader to ensure dual, end-to-end oversight for the portfolio. “The DASs are well connected and work closely with discovery, translational medicine, and late-clinical development teams,” she says.

Dillon says the role of the GCSO is critical in promoting alignment among the various regions on global positioning, as well as adoption of best practices from around the world. “As a global organization, it is important that we remain in tune with the needs of a diverse marketplace across North and Latin America, EMEA, and Asia Pacific. The GCSO facilitates regional collaboration and makes sure our approaches to development, marketing, medical affairs, and other activities are tailored accordingly to extend the reach of our medicines to patient populations on a global scale.”

A critical component of the R&D-commercial interchange is addressing the needs and demands of the payer constituency. “Increasingly, market access can represent a major challenge for new and existing projects, and ensuring our development plans are well aligned to the future needs of all stakeholders, including payers and reimbursement authorities, will help ensure that patients receive the treatments that they need.” When important for the gatekeepers, comparison trials that prove a product’s superior benefits and cost-advantages are one example of development reflecting commercial input.

Once a product achieves approval and enters the market, the GCSO takes the lead, but the TA team plays on. “The GCSO maintains an active role throughout the lifecycle of a product, and its people serve as coordinators across the regions and as facilitators of several postmarketing registries evaluating safety and clinical outcomes for patients receiving our products.”

For example, through the medical affairs team, immunology maintains PSOLAR (Psoriasis Longitudinal Assessment and Registry), a prospective, disease-based observational study assessing patients with psoriasis who are receiving or are candidates for treatment with systemic therapies. A key component of the company’s regulatory commitment to conduct postmarketing safety monitoring for Stelara and infliximab, PSOLAR is fully enrolled with more than 12,000 patients to be followed for up to eight years. The key demographics, disease characteristics, and medication history of patients were collected at enrollment. Adverse events and efficacy data are collected longitudinally. A PSOLAR global steering committee manages epidemiological research on psoriasis and its therapies.

Postmarketing research and other commercially important input not only inform product positioning on the market but also feed back into the scientific end of drug discovery and development. “By design, it all starts within a disease area, where we see the key unmet medical need based on disease understanding and deep market insight, which drive our selection of a target, as well as the means of administering the drug and the other attributes such as biomarkers.” (See “Toward a More Perfect Diagnosis.”) But the scope of market modeling for a product points toward the future, she says.

“We need to think about the time horizon. When a drug comes to market, what will the field look like, and how may the unmet medical need change by that point? As we go down the path further in development, we keep refining the target profile.”

Facing Biosimilar Competition
At the time of our conversation, Dillon has just come from a “town hall meeting” of the Janssen Immunology team at its R&D hub in Spring House, PA, including the virtual presence of its people in La Jolla, CA; Beerse, Belgium; and other sites around the world. Such periodic gatherings serve to update the team on current developments, internal and external, that affect the organization and its efforts. At this meeting, the progress of the pipeline portfolio was discussed, as well as a more perturbing topic — the federal court decision in Boston that ruled a key patent for Remicade invalid, paving the way for a biosimilar version of the product by Pfizer. Aside from the unusual spectacle of two pharma giants locking horns over one’s intent to produce a knockoff, the decision was significant for forcing Janssen to face biosimilar competition, obviously much earlier than it wished.

“Of course, we are not in agreement with the decision, but at the same time, we’ve known that biosimilars are coming at some point, and we’ve been well prepared for that for years,” Dillon says. “We support the regulatory framework for the approval of biosimilars as long as the standards and policies are based on sound science, with the understanding of the complexities of biologics.”

But the overarching theme of the meeting extended the awareness of competition and adversity in the market even further. “We are trying to get people’s heads around how the future of healthcare may develop and affect us,” she says. “This is a recurrent theme in the conversations with our group — science is evolving at an unprecedented pace in general and in immunology, and at the same time, the whole ecosystem of healthcare is rapidly changing. We need to remain focused on being medical innovators and driving innovation. That is critical in R&D but just as much in the commercial space. The competitive nature of the market drives the science and our business forward.”

Dillon’s words somehow invoke a mental picture of the Janssen model, as displayed by Janssen Immunology. Perhaps the idea of keeping its groups relatively small and specialized inside the giant protective dome of a corporation has traction. Smaller groups, say the size of Dr. Paul’s original Janssen, tend to think boldly and urgently; big companies can have a longer-term vision, if they are also brave enough to use it.

3 Big Hurdles

We asked Sue Dillon, head of Janssen Immunology — “What are the three biggest changes or challenges your group faces for the future?” Dillon answers:

We seek opportunities to achieve the following goals:

  • Remain at the forefront of science with the breakneck speed at which R&D and technology are advancing and harness the “explosion” in areas like the microbiome to drive continued innovation.
  • Unlock the early triggers and signs of immune diseases to induce tolerance or even intervene before patients develop active disease — move toward prevention, interception, and cure.
  • Design development programs to satisfy regulators and payers, empower patients and physicians, and provide postapproval, real-world evidence to substantiate the value any new medicine brings.

Paying & Pricing

The thoughts of Janssen Immunology’s leader Sue Dillon on the central issues in the drug-pricing controversy shed some light on the company’s approach:

We consider three fundamental components when pricing our medicines:

VALUE. We consider the value of our products to patients and to society as a whole, including elements important to governments and other payers, such as clinical benefits and risks versus the standard of care, improvements in the patient experience (better quality of life and higher satisfaction with treatment), and impact on societal and economic factors (total cost of care, disability and productivity, and the benefits to society of reducing caregiver burden).

INCENTIVE FOR INNOVATION. In order to continue to incentivize investors to fund biomedical innovation, we must provide returns in line with their expectations. We support the model that ensures that when our IP protections and regulatory exclusivities end, generics and biosimilars are introduced, generally leading to significant decreases in price.

ACCESS AND AFFORDABILITY. Recognizing that economic and healthcare circumstances differ vastly and that cost can often be a barrier to access, we use a wide variety of approaches, appropriate to the specific reimbursement systems and legal guidelines of various countries, to ensure and sustain broader access to our medicines. Using tools such as tiered pricing and partnerships with public health organizations, we strive to engage stakeholders to help achieve broad and timely access to our medicines in a way that is affordable locally. We are working with payers to explore innovative approaches that tie reimbursement to health outcomes, reflecting the true value our medicines bring to patients and the healthcare system.

We want our drugs to remain broadly accessible by ensuring the net cost is in line with other currently available biologic therapies. We offer a number of patient support programs to ensure broad accessibility, helping support eligible uninsured and underinsured patients to have access to treatment through the Johnson & Johnson Patient Assistance Foundation. In 2015, Janssen helped approximately 762,000 commercially insured patients to significantly reduce out-of-pocket spend for its medications.

In 2015, Janssen donated medicines and funding to enable the Foundation to provide medicines to approximately 100,000 U.S. patients without adequate financial resources and prescription coverage.

Immunology Into IO And New Territories

Perhaps the strongest siren call for a wider therapeutic focus by Janssen Immunology would be in immuno-oncology (IO), where Janssen appears to lag behind other large companies. Head of Janssen Immunology, Sue Dillon, gives the following explanation of how her group will contribute to the company’s crossover into IO, as well as other new therapeutic areas.

Immuno-oncology is among the most active areas of R&D investment at Janssen, with 15 immuno-oncology compounds currently in our pipeline. Our IO work is being led by my counterpart, Peter Lebowitz, M.D., Ph.D., who heads up the Janssen Oncology TA (therapeutic area). Realizing that the majority of patients are not responding to currently approved IO agents, his team is pursuing novel approaches or modalities. The result is a pipeline that is highly competitive across the industry. We believe we will expand the impact of immunooncology by focusing on the next wave of new, innovative modalities.

Because of our expertise, we look at immunology holistically. Indeed, the targets for the checkpoint inhibitors are on our radar screen as potential targets for autoimmune disease, with the idea of blocking costimulatory targets or creating agonists for co-inhibitory receptors to dampen T cell activation (i.e., the opposite of oncology). We are also working across the TAs to better understand the opportunity of immunological underpinnings in a multitude of diseases, including treatment-resistant depression, for example.

To further explore the role of innate and adaptive immunity in multiple diseases, we’ve recently formed a group called Janssen Immunosciences, which aims to bring immunology expertise and capabilities across the TAs. This is led by Murray McKinnon, who also currently heads Immunology Discovery. Together with his colleague Anish Suri, who is based in Beerse, Belgium, he has established the Immune Repertoire Center where they are mapping the immune repertoire for disease monitoring, interception, and immunomodulation of T-cell mediated diseases.

Toward A More Perfect Diagnosis

Drug/device combinations have been a key focus of Janssen and Janssen Immunology, headed by Sue Dillon, who describes how the coordination of drug and diagnostic development has progressed in her group in recent years.

We continue to make progress in the area of drug and diagnostic development by incorporating biomarkers that may predict drug response or aid in segmenting patient subpopulations into many of our clinical-trial designs. We are also exploring digital health applications for clinical trials and to further enhance drug products. For example, RA-RA, or remote assessment in RA (rheumatoid arthritis), is a new digital biomarker program implemented by Janssen that uses wearable, commercially available activity monitors and a smartphone mobile app aligned with the cloud to study the daily fluctuations in disease for patients with active RA. This program represents one of our many initiatives to integrate digital technology into our work. Overall, our strategic biomarker discovery work and our digital health applications aim to understand unmet needs at the molecular, cellular, and patient level, trying to predict responses and create more personalized treatment programs.