The heart and kidneys appear to have little in common—except when they go wrong. Between 40 and 50 percent of people with heart failure also suffer from chronic kidney disease (CKD). Cardiovascular problems account for up to half of late-stage CKD deaths. Add interconnected metabolic diseases such as diabetes, and the results account for poor health outcomes in hundreds of millions of people around the world.
Taken together, CVRM (cardiovascular, renal and metabolic) diseases comprise the most important medical acronym you may have never heard of. In the U.S., for example, more than 90 percent of people with type 2 diabetes have at least one other CVRM disease, and more than 30 percent of heart failure patients have chronic kidney disease. And because different CVRM conditions often interact to quicken disease progression, this can affect the prognosis and quality of life of patients.
Yet these same interconnections may also offer new routes for therapies. A single medicine or combination of medicines can have dual mechanisms and act on common biological pathways to treat multiple conditions simultaneously. Some medicines for type 2 diabetes, for example, are now also recommended for both heart failure and chronic kidney disease.
Successfully treating one CVRM condition can sometimes ease the symptoms of another. Improving kidney function, for instance, can lower blood pressure and reduce the risk of heart failure.
“There are potentially life-saving therapies for individual CVRM conditions,” says Regina Fritsche Danielson, who leads research and early development for CVRM at the biopharmaceutical company AstraZeneca. But “real-world evidence from patient cohorts shows that many patients are not responding well to the current standard-of-care therapies.”
Unmet needs
Patients who are often treated for one condition, but not holistically with other related conditions, are sometimes undertreated or undiagnosed, Fritsche Danielson says. And some patients with multiple CVRM conditions take several separate medicines, which often reduces their compliance.
For other patients, a first-line drug might pose unwanted side effects. For example, mineralocorticoid receptor antagonists used to control blood pressure for CKD may also raise blood potassium levels and require additional patient monitoring.
By focusing on CVRM disease interconnections, AstraZeneca is seeking to develop solutions that address individual diseases while delivering more holistic benefits, Fritsche Danielson says.
One example aims to improve kidney function through complementary approaches: targeting hypertension and CKD, in combination with increasing glucose removal by the kidneys.
Years of investigation into individual CVRM diseases has put AstraZeneca in a “leading position,” says Herbert Waldmann, former head of the chemical biology department at the Max Planck Institute of Molecular Physiology in Dortmund, Germany, and a paid scientific advisor to AstraZeneca. “They have a strong, fully functional unit that looks at this disease area, which is one of the industry’s biggest and most important.”
AI is helping researchers understand and predict how candidate drug molecules bind to target proteins in the cell.
AstraZeneca
Molecular insights
Targeted CVRM drug discovery relies in part on data from 20 years of AstraZeneca’s clinical trials. “We have such strong insights from our medical teams talking to and treating patients,” says Malin Lemurell, who leads medicinal chemistry for CVRM diseases.
The new approach is also based on research tracing illness at the molecular level, which continues today using several advanced techniques. These include high-throughput screening to analyze many samples at once and cryo-electron microscopy, which builds detailed 3D maps of protein structures and how potential drug molecules bind to them.
Artificial intelligence and machine learning play a critical role in unravelling how these proteins might bind to one another and interact. This can help researchers understand how an illness evolves, or which types of drugs might influence the progression of one or more CVRM diseases.
It can also speed up drug discovery by designing novel small molecules from scratch that are likely to work with the proteins researchers want to influence. This lets them rapidly identify novel compounds and optimize the properties of candidate molecules for clinical testing, to improve the overall chance that these candidate molecules progress to clinical trials.
“We have been able to crack some very difficult targets in pathways we have been investigating for a long time, to understand how they work at a molecular level, and move possible therapies into the clinic,” Lemurell says. These include experimental drugs targeting precision pathways for heart failure, the incretin pathway for metabolic health, and lipid-lowering pathways for cardiovascular disease.
Better predictions
Once promising molecules have been created, they need preclinical testing. Advanced tissue-culture methods help. These methods produce stem-cell-derived, three-dimensional organoids that emulate key physiological aspects of real human kidneys or other vital organs, including fluidic channels lined with living cells.
Testing medicines on advanced cell systems such as human organoids more accurately predicts outcomes in humans than lab animal testing does. AI models advance the process by analyzing data from such studies to predict the best combinations of medicines, their doses, and how they will accumulate and break down in the human body. Such studies rule out some potential drug compounds early in the pipeline. This makes drug discovery faster and more efficient, and it can help improve clinical-trial safety outcomes.
“AI insights and data-driven predictions now inform all our drug discovery and early clinical trials,” Lemurell says. “I've seen so many good examples now that I'm convinced it works.”
Waldmann concurs. “When a new target comes up, the question is increasingly not, ‘can we address it?,’ but, ‘which modality are we going to use?’”
These new research tools have raised hopes of better outcomes for many CVRM diseases—and not just with small-molecule drugs.
AstraZeneca is working with Ionis Pharmaceuticals in CKD affecting people of African ancestry. The disease is caused by two variants of a gene called Apol1 that distort production of a critical kidney protein. The plan is to find a way to screen CKD patients for the rogue variant and block its increased production with an antisense strand of modified RNA.
With new research tools in hand, AstraZeneca researchers are optimistic about the future.
“We believe our CVRM expertise and rapidly advancing technologies will enable us to develop more effective medicines to fight the underlying and often interconnected drivers of these diseases,” Lemurell says.
Learn more about CVRM disease at this dedicated site from AstraZeneca.
