Kidney disease hasn’t been an area of vibrant transformation, but it is emerging as a promising and area for diagnostic and therapeutic investigation following an explosion of foundational technologies in recent years, according to speakers at BIO-Europe® Digital, held virtually October 26-29.
Kidney disease hasn’t been an area of vibrant transformation, but it is emerging as a promising and area for diagnostic and therapeutic investigation following an explosion of foundational technologies in recent years, according to speakers at BIO-Europe® Digital, held virtually October 26-29.
Now that chronic kidney disease can be defined in genetic and molecular terms rather than in broad histological terms, precision therapeutics are possible for kidney disease.
That’s a big reason why Johnson & Johnson (J&J) Innovation shifted its focus from obesity to kidney disease in the past few years, why Chinook Therapeutics focuses exclusively on kidney disease and why Vertex Pharmaceuticals and Evotec are devoting significant attention to this global disease.
“There was a lack of understanding of the disease,” Lars Erwig, VP, CVM innovation at Johnson & Johnson Innovation, said.
Therapies were non-specific, addressing symptoms rather than underlying causes of the disease.
“This isn’t one disease entity,” he said. “Patients with IgA nephropathy have very different courses of disease. Only 30% progress to end stage renal disease. Identifying these patients is more important than identifying the right drug target,” because the drug must be applied to the right patient to be effective. “Now, all our efforts at J&J are directed at disease modifying therapies that halt the progression of disease – fibrosis, for example,” Erwig said.
Reversing the course of kidney diseases is a realistic possibility. “Regenerative therapies, including cell therapies, gene therapies and iPSC-derived therapies, are in the clinic for kidney disease, as well as for cancer and other conditions,” Olivier Radresa, VP, nephrology, Evotec, pointed out. “This is a very active area of research,” and is a significant change from primary outcomes that sought only to stabilize the disease.
These innovative therapies are based on the “increased understanding of the molecular and genetic drivers of disease that enable targeted therapies with disease-modifying potential,” said Andrew King, head of discovery and translational medicine at Chinook Therapeutics.
APOL1, for example, is a causal genetic variant that has disease-modifying potential. Its role in severe kidney disease wasn’t identified until 2010. A Vertex compound, VX-147, aims to inhibit APOL1. It is in Phase II trials for kidney disease.
Chinook is advancing the precision therapeutics Atrasentan (entering Phase III trials in 2021) and BION-1301 (now in Phase I trials) to target IgA nephropathy. Atrasentan, which Chinook licensed from AbbVie, is a small molecule inhibitor of the endothelin A receptor. BION-1301 is a humanized IgG4 monoclonal antibody that prevents a proliferation-inducing ligand (APRIL) from binding to the BCMA and TACI receptors, thus preventing the initiating events that lead to IgA complex formation.
“Chronic kidney disease is a global challenge,” King emphasized. “In particular, in Asia there is extremely high unmet need because of the incidence and prevalence of a variety of kidney diseases. IgA nephropathy, for example, has a high incidence throughout Asia – especially in China – and shows evidence of a more aggressive phenotype in Asian populations, so it progresses rapidly.”
In response to such population differences, companies are developing therapeutics with global applications in mind. “Vertex is focused on APOL1,” Anne Fortier, director, discovery biology, Vertex, said. “It (affects) not only African-American, but also African-European, and African Caribbean (and native African) patients, so we have to look at the distribution of those alleles. Asia is one area where (the APOL1 genetic variant) is really prevalent.” That means including those populations in clinical trial designs, she added.
Evotec is looking to extend its cohort of mostly European and Caucasian patients into Asia, to identify subpopulation characteristics that are associated with kidney disease.
As advanced technologies continue to be applied to kidney disease, “The most important contribution of the next generation of technology will be the better identification of the underlying cases of the disease, and the identification of biomarkers,” Fortier predicted. Biomarkers have the potential to alert people early in the disease, so it can be treated.
Artificial intelligence and machine learning provide the computational power needed to decipher and correlate the data in large biobanks that combine patient biopsies with large ‘omics approaches. With tens of millions of reads per sample, “The limitation is making sense of it all,” Radresa emphasized.
Applying AI and machine learning, “can identify subpopulations of patients most likely to benefit from specific therapies,” Erwig said. “That will make a great difference.” On the business side, he suggested using AI to identify all the companies engaged in this research to increase J&J’s partnering network.
Partnering is a goal for each of these speakers. “We’re in the market for making deals with biotech and academia to develop this space, and have the external innovation system set up,” J&J’s Erwig said.
Likewise, Radresa added, “Evotec Innovate was formed to enable small companies to identify the best pathways, targets, biomarkers, and patients to progress their drugs to the clinic. We’re looking to establish new collaborations.”
Chinook has been very active in in-licensing and partnering, “and we continue to evaluate opportunities to add to our kidney disease discovery program,” King said. “We’re particularly interested in early stage programs – both preclinical and discovery – targeting the key causal molecular pathways.”
Chronic kidney disease has been relatively neglected area of drug development but, they agreed, is about to experience a burst of activity and promising innovations.
