Rare Community Profiles
Rare Community Profiles is a new Patient Worthy article series of long-form interviews featuring various stakeholders in the rare disease community, such as patients, their families, advocates, scientists, and more.
Dr. Jonathan Barratt Discusses Phase 2b Data on Atacicept for IgA Nephropathy
In early 2023, Vera Therapeutics announced results from a prespecified per-protocol analysis of the Phase 2b ORIGIN clinical study. Within this study, Vera Therapeutics was evaluating atacicept for patients living with IgA nephropathy (IgAN), a chronic kidney disease that can progress to kidney failure. Atacicept has the potential to change the treatment landscape, as there are no effective IgAN treatment options at the moment. Improving outcomes within this sphere relies on the development of novel and effective therapeutics.
Dr. Jonathan Barratt, PhD, FRCP, The Mayer Professor of Renal Medicine, University of Leicester was one of the study’s Principal Investigators. Recently, he spoke with Patient Worthy about IgAN, the need for advances within the nephrology realm, the ORIGIN study, and what he gleaned from the results.
JL: To begin, tell me about yourself and your background!
Dr. Barratt: I’m a clinical nephrologist, so I look after patients with a range of kidney diseases, particularly glomerular diseases. I am also a researcher with an interest in why glomerular diseases develop, the triggers that exist, and new targets that we can use to design treatments and attempted cures for glomerular diseases that commonly affect young people and carry a high risk of developing kidney failure in the future.
What led you to pursue a career in renal medicine? What sparked your interest in this field?
I enjoy the combination of science, immunology, and disease understanding. Nephrology lends itself to that because we are routinely looking at kidney biopsies to see, firsthand, what’s happening in the kidneys themselves. We can relate that to how patients are behaving in terms of symptoms, what we can see developing, and complications. There’s a very clear link between the science, what’s happening internally, and what we see externally with patients.
I get the opportunity to deal with people who are acutely unwell and also develop relationships with patients who have a more slowly progressing disease; these patients are some that I will look after for the rest of their lives.
In your words, what is IgA nephropathy (IgAN)?
IgA nephropathy is a disease of the kidneys or, more specifically, the kidneys’ filters. Each kidney has around one million filters that are continuously filtering the blood to produce urine and getting rid of the toxic substances that the body creates during the day. When these filters are damaged, this can cause scarring and an inability to remove these toxins. IgA nephropathy is a disease caused by the deposition of IgA protein in these filters. Everyone has IgA proteins; it’s a normal antibody. But in patients with IgAN, the protein is more sticky. It sticks to itself and other proteins in circulation, forming larger protein lumps that essentially ‘sludge up’ the kidneys’ filters. When these filters are damaged, they can cause scarring and, essentially, loss of ability to remove these toxins.
If you can imagine big “clumps” accumulating in a sieve, that’s what it looks like in the kidneys. These proteins accumulate in the glomeruli — the sieves of the kidneys — and trigger reactions like inflammation, cell damage, and glomerular damage. Ultimately, this leads to loss of function and kidney failure. The problem is that we’re unable to regenerate these filters. Once they’re lost, they’re lost forever. When you start with a certain number of filters, your risk of kidney failure in the future increases as soon as you start losing them.
Why is it important to develop or pursue new therapeutic options for IgAN?
The bottom line is that we currently have no effective treatments. We have some general treatments that are given to all patients with kidney diseases. But there are no specific treatments to reduce the amount of IgA that builds up in circulation and deposits in the filters. There’s a lot more work to do until this disease can be cured.
What does it mean to be a Principal Investigator for clinical studies, and what are your responsibilities?
My job as a nephrologist is to care for patients to the best of my ability. I can use currently available drugs, but we know that they’re not very effective. So the only way I can gain access to new and exciting therapies for my patients is by being involved in clinical studies and offering patients the opportunity to join clinical studies. I see that as an essential role of any doctor, but particularly nephrologists.
I want to be a principal investigator because that means my patients in Leicester in the United Kingdom can become involved in research to potentially change the way we manage IgAN. It means they’ll be first to gain access to drugs that potentially may help them—and on top of that, they’re contributing to better care for all people with IgAN. Not every patient has to be involved or will choose to be involved, but I feel it’s beholden on us to offer the opportunity to take part.
The importance of being a Principal Investigator is ensuring that the study is delivered carefully, safely, and to a high quality. My responsibility in Leicester is to ensure that the studies are delivered to the highest possible standards, which means that they protect patient safety and ensure that the study generates robust, solid, and reliable results that can be used to decide drug approvals and global availability.
Moving to the prespecified PP analysis of the ORIGIN trial – what is atacicept?
Atacicept is a new drug that is designed to target the cells that produce the abnormal form of IgA. These cells, called B cells, are part of our immune system and need two chemical factors, almost like nutrients, to keep them functioning. We call these BAFF and APRIL. Atacicept binds to these chemicals in circulation and tissue and facilitates their removal from the system before they can activate the B cells. Essentially, atacicept deprives B cells from important growth factors that they need to survive. The B cells are then unable to behave normally or produce abnormal IgA.
The analysis showed that patients receiving 150mg atacicept achieved a delta of 48% vs. placebo in mean proteinuria reduction. What does that mean?
The study found that atacicept is capable of reducing abnormal IgA; it’s very good at removing IgA from circulation. We also saw that atacicept reduces protein in the urine (proteinuria), which is an indicator of how inflamed those filters are. Atacicept was able to decrease—by nearly half—the amount of protein leaking out in the urine. This tells me that it’s having a massive impact on the degree of inflammation in the kidneys. It’s doing so by stopping abnormal IgA protein deposits in the filters. The drug is going directly to the source of the problem; there is no further deposit of IgA complexes within the glomeruli, and the trigger for inflammation and scarring has been switched off.
What were some of the most interesting or impactful pieces of data from the study?
We always get focused on how well the drug works in terms of reducing proteinuria, but it’s more important to understand the drug’s safety and tolerability. Safety data showed that atacicept was well-tolerated. Patients didn’t want to stop taking the drug. The risk of infections, which is the major concern for any treatment affecting the immune system, did not greatly increase. This shows that, in addition to being effective, it is safe and well-tolerated. I believe that atacicept could practically be used in daily clinical practice.
How could atacicept change the treatment landscape for IgAN?
Atacicept offers the ability to turn off the production of pathogenic IgA at the source. It would be groundbreaking if we could do that in a safe, effective, and predictable way. We could then eventually get this disease under complete control. If we can do that, we can stop the loss of kidney function and patients will be far less likely to develop kidney failure.
What further IgAN research do you believe should be performed?
I think that we’ve made great strides in our understanding of IgA nephropathy, but we’ve got more work to do. We need to better understand where the cells are that are producing abnormal IgA—are they in a particular spot in the body, or are they everywhere? We need to understand what makes IgA proteins clump together and what pathways are activated when those deposits form in the kidneys.
IgA nephropathy behaves differently in different parts of the world. We don’t really understand why it is more common and more likely to cause kidney failure in East and Southeast Asia, whereas you’re less likely to have kidney failure if you’re Caucasian and living in North America or Europe. Learning about the global distribution of IgAN could help us understand the disease at a basic level.
On a more targeted level, of course, I look forward to taking part in the Phase 3 atacicept study and seeing what we can do in determining whether this treatment can and should be approved.