Chronic kidney disease: treating a silent killer

In November, NICE backed NHS use of AstraZeneca’s diabetes and heart failure drug Forxiga for the treatment of chronic kidney disease. pharmaphorum caught up with AZ’s Joris Silon to discuss unmet needs in the condition.

“Many times, I have talked to nephrologists who take care of patients with chronic kidney disease in the later stages, and they have a very simple message – and that is, if we really want to do something for these patients then we need to intervene earlier,” says Joris Silon, senior vice president of AstraZeneca’s cardiovascular, renal and metabolism biopharmaceuticals business unit.

The pharma firm has done just that with the recent approval and launch of Forxiga (dapagliflozin). The oral first-in-class drug can be administered in the early stages of chronic kidney disease (CKD) and has been shown to delay disease progression. Says Silon: “Many people have said this is one of the most important interventions since the advent of dialysis.”

CKD is one of the leading causes of death worldwide, a progressive condition that worsens over time. The disease affects almost one in ten people, equating to an estimated 47 million people in Europe alone. It’s described as a silent killer because most patients don’t realise they have the disease until the later stages when symptoms are more severe and the risk of serious complications and kidney failure increases. In fact, AstraZeneca’s research shows 90% of people are unaware they have the condition. Even worse, CKD is grossly undiagnosed.

“This is a disease where we need to intervene in the early stages to avoid progression to kidney failure, cardiovascular complications and to avoid patients requiring dialysis or kidney transplants, which are invasive, time-consuming and expensive,” Silon says.

A “bold step” to understanding CKD treatment

Enter Forxiga – or Farxiga in the US. In March last year, AstraZeneca halted its phase III DAPA-CKD trial after interim results showed there was a benefit “earlier than originally anticipated”. Trials show the combined risk of worsening kidney function, end-stage kidney disease onset and kidney disease or cardiovascular-related death was cut by 39% in patients with chronic kidney disease (with or without type 2 diabetes) compared to placebo. In addition, the risk to all-cause mortality was reduced by 31% compared with placebo.

According to Silon, the results are exciting. “We’re hoping we can have a big impact on these patients’ lives in terms of avoiding hospitalisations, avoiding co-morbidities and, in turn, we’re also helping the whole healthcare system.”

But what is also exciting is the evolution of the drug because Forxiga didn’t start life as a drug for chronic kidney disease. It was initially developed for type 2 diabetes and was approved for this indication in 2014. “But we quickly understood the mechanisms that it could prevent the most frequent co-morbidities of type 2 diabetes, which are cardio-renal, meaning heart failure and chronic kidney disease,” says Silon.

The pharma giant initiated a series of trials, which Silon calls a “bold step”, to better understand and elucidate the mechanisms of action and to see whether the drug could do more for patients outside of type 2 diabetes. The DAPA-HF and DAPA-CKD trials were launched, including patients with and without type 2 diabetes. The findings showed that mortality and hospitalisations for these diseases were reduced for patients with and without type 2 diabetes. In 2019, the drug was approved to reduce the risk of hospitalisation for heart failure in patients with type 2 diabetes and earlier this year, Forxiga got the thumbs up for chronic kidney disease.

Silon says the science highlights how interconnected these three diseases are. “From a drug that was initially a type 2 diabetes drug, Forxiga is now firmly establishing itself as a heart failure drug and now as a drug for chronic kidney disease… It all starts with following the signs and putting the right trials in place to prove the drug is working in these different indications.”

“The important thing is that guidelines embrace the change and embrace the scientific innovation, and guidelines are being updated to reflect this innovation for patients both with heart failure and with chronic kidney disease”

Embracing scientific innovation

The expansion in indications is a boon for AstraZeneca and analysts believe Forxiga could rake in several billions of dollars a year, especially as the drug is likely to become a new standard treatment of care. Having the drug broadly available in type 2 diabetes helps for a faster uptake in CKD versus a new launch, Silon says, but adds that reframing a type 2 diabetes drug as a heart failure drug and now a CKD drug also comes with challenges.

“The important thing is that guidelines embrace the change and embrace the scientific innovation, and guidelines are being updated to reflect this innovation for patients both with heart failure and with chronic kidney disease,” he explains.

But updating guidelines is only the start of the process – after this, the hard work really starts, says Silon. That’s where education and disease awareness comes in. The company is particularly focused on a big push in primary care in a bid to encourage doctors to catch CKD earlier in disease progression.

“It’s about making sure physicians, and all stakeholders in the ecosystem are aware of these changes so that ultimately patients can benefit,” he notes.

Indeed, Silon says it’s not just about finding new medicines. AstraZeneca is also advocating for routine testing and earlier interventions. It’s about increasing awareness so that patients are more aware to ask about it, primary care doctors are more likely to test for kidney function, and healthcare systems are more likely to put CKD on a priority list. Silon says this is happening to some degree, but it requires a multi-pronged approach and collaboration.

Boosting awareness of CKD

For AstraZeneca’s part, it is working with the International Society of Nephrology in a global campaign to increase the awareness of CKD and the importance of early testing. “It’s a multi-pronged approach,” says Silon. “One element alone is not going to make a solution, but if we all put our best foot forward, I think we can make a big difference very fast.”

With this in mind, Silon notes the firm’s R&D investment in CKD and how the science indicates that it is not a unified disease between patients. “We’re going more into an area of personalised healthcare – can we look at biomarkers and see whether a biomarker can identify you as a certain subtype of chronic kidney disease and then have a specific solution for you,” he notes when explaining how the CKD space will develop. “While our drug is a drug that works quite broadly, maybe in the future we’ll have more personalised approaches. That is needed for chronic kidney disease to get it to the next level.”