Aiming Precision Medicine at Chronic Diseases

Chronic diseases cover a wide range of medical conditions from asthma and diabetes to gastrointestinal and heart problems. As the U.S. Center for Disease Control and Prevention (CDC) notes: “Chronic diseases are defined broadly as conditions that last 1 year or more and require ongoing medical attention or limit activities of daily living or both.”¹ The CDC adds that chronic diseases are the “leading drivers of the nation’s $4.1 trillion in annual health care costs.” Consequently, applying precision medicine to these conditions could benefit many patients and reduce the costs of medical care.

Nonetheless, scientists and clinicians face a key challenge in treating chronic diseases. “They’re very biologically complex, and they are driven by multiple mechanisms,” says Adam Platt, PhD, vice president and head of respiratory and immunology translational science and experimental medicine at AstraZeneca. “Some would argue a lot of the common diseases we work on—such as asthma, chronic obstructive pulmonary diseases, and chronic kidney disease—are actually syndromes made of several different diseases with different molecular drivers.” Consequently, two people with asthma, for example, could need precision medicines that target different mechanisms.

So far, biopharmaceutical companies post a poor track record in developing new treatments for chronic diseases. In thinking about the number of interventional clinical studies and the drug approvals for chronic diseases, Platt says: “There isn’t really a brilliant return on investment, which suggests we’re doing something wrong.”

Adding precision

The traditional approach to finding treatments for chronic diseases is the problem. “Conventional evidence-based medicine relies largely on evidence derived for the average individual within a larger cohort,” says Paul Franks, PhD, director of translational medicine at the Novo Nordisk Foundation, which is a private philanthropic foundation that supports research and education in many areas, including precision medicine. “No one is ‘Mr. or Mrs. average,’ and the extent to which one is similar or different from this average affects how well conventional evidence-based medicine works for a given person,” Franks says.

In biologically complex chronic diseases, precision medicine aims to address those differences among patients. To do that, Franks explains, precision medicine “involves the intelligent analysis of data about a person’s biology, behavior, clinical characteristics, and other contextual features.” The aim, he says is to “refine the characterization of disease and optimize its prediction, prevention, diagnosis, treatment, or prognosis.”

Many factors drive the need to develop precision medicines and diagnostics for chronic diseases. As the Novo Nordisk Foundation pointed out in a white paper: “Breakthroughs in precision medicine are not merely of academic interest, but, more importantly, necessary for humanity, if the burgeoning health demands of global populations are to be equitably addressed.”²

Targeting the biology

Gaining precision and limiting side effects requires a molecular approach to clinical trials and treatments. “The real clincher here is about moving away from trial-and-error based approaches to treatment to approaches that allow us to target the right treatment to the right patient, first time,” says Maria Orr, PhD, head of precision medicine for biopharmaceuticals at AstraZeneca. “If we understand what causes the diseases we’re trying to treat, and then we target therapies to the root cause, then we’ve got a much better chance of being able to meet our precision medicine ambitions.”

Currently, AstraZeneca focuses largely on precision-medicine molecules. “We’re seeing that 90% of our pipeline is exploring that precision-medicine approach,” Orr says. Much of this work revolves around the biology of chronic disease. “If you don’t start with fundamental biology, you’re never going to be able to get to what we need to do for patients,” Orr says. “Once you get to understand this biology, you’ve got to develop targeted agents and identify approaches for selecting the patients which need to be explored in your clinical trials to deliver the data that proves your precision medicine hypothesis.”

To find those patients, scientists need access to the right biological information. “It’s the availability of large cohorts which allows us to explore that biology,” Platt says. “So we joined a consortium to exome sequence the UK Biobank, which is 500,000 patients.” From that, Platt and his colleagues gained access to the exomes of more than 20,000 people with asthma and more than 200,000 people without respiratory conditions who can be used as controls. “This has formed the basis of the precision medicine strategy for one of our asthma molecules, which is in Phase 2,” he says. “Because we’ve been able to explore the genetics in large numbers, we can go into a Phase 2 with some confidence around our precision-medicine proposition.”

Industrial and academic scientists are exploring precision medicine for a range of chronic diseases.

Dealing with diabetes

Diabetes is one of the most common chronic diseases. According to the International Diabetes Federation, “537 million adults are now living with diabetes worldwide,” and this disease is on the rise.³

International groups are exploring the use of precision medicine to treat diabetes. In 2020, for example, Franks and his colleagues reported on a collaboration between the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).⁴ Franks describes this work as “comprehensive systematic evidence reviews across all key areas of precision diabetes medicine.” The outcome, however, is not expected to be published until late 2023.

Nonetheless, Franks notes that the “TriMaster trial is the only completed [randomized clinical trial] to have specifically tested a precision therapeutics approach for diabetes treatment.” This trial stratified patients based on body mass index and estimated glomerular filtration rate to determine the best of three treatments based on various metrics, including blood sugar level (HbA1c), side effects, and patient preference. Although the results of this study have not been published, trial statistician Beverley Shields, PhD, of the University of Exeter Medical School reported on the results at the 2021 EASD meeting.⁵ She stated: “Different patients preferred different drugs… The preferred drug was the one that was generally associated with the lower HbA1c.”

Precisely treating pediatric inflammatory bowel disease

From 2007 to 2016, the prevalence of pediatric inflammatory bowel disease (IBD) increased by 133% in the United States.⁶ This chronic inflammatory disorder of the bowel most commonly emerges as Crohn’s disease or ulcerative colitis. Bringing precision treatment to pediatric IBD is a specialty of Marla Dubinsky, MD, professor of pediatrics and medicine at the Icahn School Of Medicine in Mount Sinai, New York.⁷

“What’s unique about pediatric IBD is the fact that the younger you are when you’re diagnosed, there’s a longer duration of having a chronic incurable condition,” Dubinsky says. “We also know that pediatric patients tend to present with more advanced or what we call more aggressive phenotypes.” According to Dubinsky, ulcerative colitis for example, impacts the entire colon (pancolitis) in about 80% of children at presentation, yet only a minority of adults present with pancolitis. “In both pediatric and adult onset IBD, controlling inflammation quickly and effectively is our goal, however there is an even greater urgency in children as ongoing inflammation can delay growth and development,” Dubinsky says.

One way to do that is by understanding the main drivers of inflammation in the intestine and targeting these cytokines with therapies that are designed to impact specific immune cells and pathways. One such cytokine is tumor necrosis factor (TNF), and it was the first target of monoclonal antibodies approved for IBD. These advanced therapies are part of the class of therapies known as biologics. In other words, there are therapies that are targeted to an understanding of the underlying biology characterizing inflammation. There are two anti-TNF agents currently approved for children, and clinicians hope that there will be other non-TNF biologics available to children just like there is for adults with IBD.

“Part of the precision is figuring out who needs an advanced therapy,” Dubinsky explains. Precise timing also matters, especially in pediatric IBD. “If you start a drug too late in a disease where you get progressive bowel wall damage and fibrosis or scarring, we don’t have any way to reverse scar tissue,” Dubinsky says. “So if you wait too long and don’t take advantage of that window of opportunity, you’re pretty well resulting in a surgical outcome for sure for a Crohn’s patient.”

The dosage is also crucial. “Finding the right dose and keeping track of the drug concentrations may even be more relevant in children as compared to adults because as you grow your volume of distribution changes, and younger patients clear a biologic therapy faster, which means you need a lot more drug,” Dubinsky says. With the wrong dose, a young person can develop antibodies to an anti-TNF drug, which means they no longer tolerate the therapy and renders the drug ineffective.

Dubinsky envisions treating pediatric IBD upstream of TNF. This could include targeting a range of interleukin pathways. At Digestive Disease Week in May, Dubinsky presented Phase 3 data on the Eli Lilly drug mirikizumab.⁸ She says that mirikizumab “is an absolutely incredible advanced therapeutic that even worked with people who had failed multiple biologics.” She adds, “Going upstream and understanding these precise biologic pathways will lead to better treatment outcomes that are also safer.”

Stopping the burn

Precision medicine might even address rare diseases with no existing treatments. For example, inherited erythromelalgia (IEM)—also known as burning man syndrome—causes chronic pain that feels like burning in the hands and feet, and common pain killers fail to relieve the symptoms.

“IEM is caused by mutations in the SCN9A gene, which produces the Nav1.7 sodium channel,” says Yang Yang, PhD, assistant professor of medicinal chemistry and molecular pharmacology at Purdue University. “These mutations cause the channel to stay open longer, causing pain neurons to become hyperexcitable.” So, Yang looks for ways to directly target the NAv1.7 channel. Although Yang and the Stephen Waxman, PhD, lab at Yale  University have identified more than two dozen SCN9A mutations that can cause IEM, Yang says that “clinical findings suggests that IEM cannot be treated with a one-size-fits-all approach.” So, he digs into IEM’s biology in the hopes of developing personalized treatments.

“Through trial-and-error in the clinic, doctors have found that patients with one particular SCN9A mutation, V400M, responded to a drug called carbamazepine,” Yang says. “We found that carbamazepine, an epilepsy drug, makes it harder for the Nav1.7 channel with this mutation to open, making it act more like a wild-type channel.” Using a three-dimensional structural model of human Nav1.7, Yang’s team identified the S241T mutation. “Given its proximity to the V400M mutation, we hypothesized that channels harboring this mutation would also respond to carbamazepine,” he says.

By using Axion Biosystems’ Maestro microelectrode array, Yang tested the functional consequences of these mutations in intact pain-sensing neurons, as well as the impact of various drugs. “With this system, one can execute high-throughput bioelectronic assays that can help us test many mutations with many different drugs at the same time,” Yang says.

It took a nationwide search for Yang to find two IEM patients carrying the S241T mutation, and they agreed to participate in a study. In a double-blind crossover clinical trial, a patient received a placebo or carbamazepine for six weeks and then after a two-week wash-out period, crossed over to the opposite treatment for another six weeks. “We saw improvement among three major parameters: duration of pain episodes, total pain duration, and awakenings due to pain, which all decreased in response to treatment,” Yang explains. “Moreover, our functional MRI data showed that carbamazepine reduced activity in the pain related subregion of the brain, further demonstrating, in a more objective manner, that carbamazepine has a beneficial effect on patients carrying the S241T mutation.”

Yang plans to keep using his bioelectronic assay to identify more potential treatments for patients carrying various IEM-associated mutations.

Developing digital biomarkers

In addition to unraveling the biology of chronic diseases and developing precision treatments, clinicians need biomarkers to diagnose these diseases and assess the impact of a drug. One company working on that is imvaria.

“Our Digital Biomarker Lab is a cloud-based machine learning development and testing platform built for healthcare and life sciences applications,” says Joshua Reicher, MD, co-founder of imvaria. “By re-analyzing complex medical imaging and laboratory data and correlating these data points with long-term clinical outcomes, we build and validate novel digital biomarkers to help drive earlier and better diagnoses.” For example, imvaria improved the non-invasive diagnosis of rare lung diseases with a digital biomarker called Fibresolve, and the company received FDA breakthrough designation based on multi-site validation results.

Using globally-sourced longitudinal data sets, scientists at imvaria assess a variety of digital data elements to extract the features that most strongly determine a patient’s diagnostic phenotypes. “These digital biomarkers can then be translated to predicting outcomes and helping drive patients into the right therapeutic selection based on risk stratification,” Reicher says.

Reicher points out a range of benefits of using digital biomarkers. He says that they “can better catch diseases early via automated lab and imaging data analysis; can better non-invasively diagnose these conditions consistently; and can potentially help drive better monitoring, pushing towards improved outcomes.”

Next steps for imvaria include bringing digital biomarkers into clinical trials and practice. As Reicher notes, “We are also developing additional features to help predict patient prognosis and assess the potential response to treatments.”

Convincing the community

Beyond biology, diagnostics, and treatments, other obstacles must be overcome to bring precision medicine to more chronic diseases. As Orr explains, a company also needs to “convince the regulators that we’ve got the right molecules, and that we’re selecting the right patients—that’s a big ask—and we’ve got to make sure that the payers understand that there’s a benefit to selecting the patients, getting them tested, and treating them with these precision approaches.” In thinking of those challenges, Orr sees a single solution: “The data will drive it.” So, scientists and companies will keep collecting more data to make precision medicine a reality for patients around the world with chronic diseases.

References

1. CDC. About chronic diseases.
2. Novo Nordisk Foundation. Precision medicine for cardiometabolic disease: a framework & vision for the future of precision medicine in the diagnosis, prevention & treatment of complex cardiometabolic disease.
3. International Diabetes Federation. Diabetes now affects one in 10 adults worldwide (2021).
4. Chung, W.K., Erion, K., Florez, J.C., et al. Precision medicine in diabetes: A
consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 43(7):1617–1635 (2020).
5. Shields, B. Results of the TriMaster trial (2021).
6. Ye, Y., Manne, S. MS, Treem, W.R., et al. Prevalence of inflammatory bowel disease in pediatric and adult populations: Recent estimates from large national databases in the United States, 2007–2016. Inflammatory Bowel Diseases 26(4):619–625 (2020).
7. Spencer, E., Dubinsky, M.C. Precision medicine in pediatric inflammatory bowel
disease. Pediatric Clinics of North America 68(6):1171–1190 (2021).
8. Dubinsky, M.C., Irving, P.M., Li, X., et al. Efficacy and safety of mirokozumab as
maintenance therapy in patients with moderate to severely active ulcerative colitis: Results from the Phase 3 LUCENT-2 study. Digestive Disease Week. Presentation Number: 867e. (2022).

Mike May, is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.