Are Kidney-Focused Clinical Studies Finally Hitting Their Groove? The Trials to Watch & Why

By Elise Wilfinger

08.10.2021

Elise:

Is it true that there has been a dearth of clinical trials in the kidney health space?

Katherine:

I wouldn’t say there’s been a dearth of trials, rather that we’ve experienced a long period of time when we did not have any trials that delivered new and effective therapeutics.

Fortunately, that’s changed over the past 3-5 years, especially with the initial observations coming out of the Cardiovascular Outcomes Trials that demonstrated unexpected signals for kidney protection with drugs that were initially designed to help control blood glucose, the SGLT2 inhibitors and also the GLP-1 agonists¹ (def.: these are therapeutics that stimulate the pancreas to produce more insulin after meals, promoting healthier blood glucose levels in people with type 2 diabetes).

The data on the SGLT2 inhibitors for improving multiple clinical outcomes in patients with and now even without diabetes is robust and consistent. Their effects on heart failure, kidney disease progression, cardiovascular events and death is remarkable.

Elise:

As a result of these more recent trials, have any breakthrough therapies been identified?

Katherine:

Yes, we now have breakthrough therapies with a class of medications named SGLT2 inhibitors (SGLT2i).

In fact, the results were so positive in both completed SGLT2i trials, CREDENCE, which tested canagliflozin, and DAPA-CKD, which tested dapagliflozin, that the studies were brought to a close early due to overwhelming benefit for patients.

2. In the CREDENCE trial, canagliflozin significantly reduced major cardiovascular events and kidney failure by 30% in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.
3. In the DAPA-CKD trial, use of dapagliflozin reduced the risk for kidney disease progression by 44%. It also indicated an unprecedented 30% reduction in all-cause mortality rate. Furthermore, while nearly 33% of the patients had non-diabetic forms of CKD, they similarly benefited.²

“We now have treatments that save lives and prevent kidney failure and heart complications, which is the major cause of death in these patients.”

– Katherine Tuttle

Elise:

Are these results typical for trials of this kind?

Katherine:

No, it’s actually shocking. With any chronic condition and, with any kind of intervention, a 30% reduction in key metrics is quite rare. This is an achievement equal to the development of beta blockers or medications that treat myocardial infarctions (def: another name for a heart attack).

We now have treatments that save lives and prevent kidney failure and heart complications, which is the major cause of death in these patients.

Moving forward, we must galvanize around increased patient and primary care physician awareness and detection because we now have effective therapeutics to offer.

Elise:

As it relates to these therapies, are more trials in the works today or have we moved on to other types of therapeutics?

Katherine:

There is an ongoing trial, EMPA-KIDNEY, which is multi-national, randomized, double-blind and placebo-controlled, and is investigating the effects of empagliflozin (brand name: Jardiance) on the progression of kidney disease in adults with established chronic kidney disease, with and without diabetes.

Based on early positive results of the DAPA-CKD trial, in October 2020, the FDA granted fast track designation for the investigation of dapagliflozin to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with CKD who are at risk of disease progression. On April 30, 2021 this drug was approved for CKD with or without diabetes, substantially extending the indication for this medication even for patients with a very low level of kidney function, with an estimated GFR as low as 25. Further, one-third of the patients did not have diabetic kidney disease.

Elise:

Have any therapeutics been granted a Breakthrough Designation Therapy status?

Katherine:

Yes, last year there were 22 breakthrough designations granted for new therapeutics. Other than dapagliflozin (AstraZeneca’s branded Farxiga) for CKD they were primarily for rare cancers or genetic diseases. (Side note: according to an October 2, 2020 press release, Farxiga was granted Breakthrough Designation in the US for chronic kidney disease after DAPA-CKD Phase III trial results demonstrated unprecedented reduction in the risk of kidney failure and cardiovascular or renal death in patients with chronic kidney disease, with or without type-2 diabetes. Specifically, it demonstrated that Farxiga on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo. The detailed results are here.)

“This is no longer a stagnant field”.

– Katherine Tuttle

Elise:

Are there other ongoing trials that are showing promise?

Katherine:

There are quite a few.

A multi-center, international trial, FLOW, is comparing the medication, Semaglutide vs placebo, when added to standard of care in patients with type-2 diabetes and pre-existing chronic kidney disease. In this trial, we’ll be looking to see whether the therapeutic can delay the progression of kidney impairment and lower the risk of mortality.

It will take several years for the FLOW trial to conclude, but it is critical to see the results it yields. Semaglutide is a medication with a mechanism of action that is quite distinct from SGLT2 inhibitors. It would be a complementary therapy to SGLT2i, adding yet another tool to the care toolkit.

Also, the FIDELIO-DKD study randomly assigned 5,674 patients with chronic kidney disease and diabetes to a novel mineralocorticoid receptor antagonist, finerenone, or a placebo and tracked outcomes for a median of 2.6 years. Finerenone significantly lowered the risk of kidney events by 18% and the risk of cardiovascular events by 14% compared with placebo.

“…the great news, we’ll start to deliver on the principles of precision medicine – the right treatment, for the right patient and at the right time – because we will have multiple choices.”

– Katherine Tuttle

Elise:

It seems like there is great potential with all the complementary – vs replacement – medications?

Katherine:

That’s exactly right. We’ll have medications with different indications and safety profiles which can be chosen for individual patients. In this, we’ll start to deliver on the principles of precision medicine – the right treatment, for the right patient and at the right time – because we will have, for the first time, multiple choices at our fingertips.

Elise:

Do we have any insights as to how we can address co-morbidities with the different therapeutics?

Katherine:

Yes, and this is where patient profiling comes in. There are different complications related to having kidney disease. Our primary focus is on kidney failure. But there are, for example, very high rates of cardiovascular events. None of the events are the same.

With so many different and individual characteristics exhibited patient to patient, having a selection of therapies allows us to tailor each – or a combination thereof – to the patient and their type of kidney disease and heart disease.

“The Kidney Precision Medicine Project is our form of a moonshot.”

– Katherine Tuttle

Elise:

Are there other types of clinical trials, beyond therapeutics? Maybe a kidney moonshot?

Katherine:

The Kidney Precision Medicine Project is our form of a moonshot.

It is a very ambitious project funded by the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. The project is designed to better understand the molecular underpinnings of different forms of chronic kidney disease that are not typically biopsied. In this study protocol or research biopsies are being investigated. The study will provide an understanding of the structural basis of various kidney diseases attributed to diabetes, hypertension or acute kidney injury, which is different from looking at conventional pathology or histology.

The idea here is, by identifying new molecular signatures and pathways, we’ll know more about therapeutic targets and also biomarkers. This will further help us to understand the disease processes in individual patients so that we can develop the diagnostics that would accompany various therapeutic choices.

“If we could clinically identify those patients most at risk and know which therapies would benefit them most – that would be the game changer.”

– Katherine Tuttle

Elise:

Is there one potential outcome that would take everything to a whole new level?

Katherine:

If we could clinically identify those patients at the most risk and know which therapies would benefit them most – that would be the game changer.

For example, the most common form of kidney disease is diabetic kidney disease, and we know that there is great heterogeneity, many different phenotypes. This is analogous to what we see with breast cancer; we now know that there are many different versions of breast cancer.

With the right tissue and the use of biomarkers upfront, we can implement very different patient-to-patient strategies, at an earlier stage, from a minimally-invasive lumpectomy to a bone marrow transplant or to intensive chemotherapy.

Expanding beyond traditional approaches will radically change our field.

Elise:

Are there trial learnings from other chronic disease states that could be utilized for optimizing kidney health?

Katherine:

Until now, the field with the most applicable precision medicine learning would be oncology.

Now I believe that nephrology is leading all fields in precision medicine. I think anyone would be hard pressed to find another field with this “in record-time development” of so many new and highly effective therapeutics, that improve all intermediate outcomes and a large reduction (e.g., 20-30%) in all-cause mortality.

In other fields, if we had even a 10% reduction in all-cause mortality, we would be celebrating.

“…we must reframe the conversation to be more optimistic… dialysis doesn’t have to be a destination.”

– Katherine Tuttle

Elise:

As it relates to kidney health, what else should we be discussing?

Katherine:

I love that you’re talking about kidney health.

I believe that words matter and that we need to relook at the whole lexicon surrounding kidney disease, including the elimination of the word, predialysis. That’s because with the therapies that we now have, dialysis doesn’t have to be a destination.  We must stop thinking about nephrology as a field that treats end-stage kidney disease.

Rather, we must reframe the conversation to be more optimistic, communicating to patients that we now have effective treatments which can help preserve kidney function and save lives.

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