Drugs for IgA nephropathy on the rise in the clinic

IgA nephropathy, a chronic kidney disease, is a condition that many scientists have been trying to cure over the years. While there still exists no cure, advancements in the field have been plenty in recent times. As we observed IgA Nephropathy Awareness Day on May 14th, let us take a look at drug approvals and ongoing clinical trials for new treatment options that aim to make patient lives better.

IgA nephropathy is a progressive autoimmune disease that occurs when there is a buildup of the blood protein immunoglobulin A (IgA). This protein is crucial for fighting infection, and people who are deficient in this protein are more likely to get frequent infections. However, if too many of these proteins accumulate in the kidneys, it can damage the part of the kidneys that filters urine – the glomerulus. 

Many people with the condition don’t realize they have it and go untreated as they tend to have little to no symptoms early on. That’s why it is called a silent disease, explained Renée Aguiar-Lucander, chief executive officer (CEO) of Swedish biotech Calliditas. 

“You’re often not in pain, there’s no edema (swelling caused by fluid buildup in tissues) or eczema (itchy, dry, sore skin) that’s associated with the disease,” said Aguiar-Lucander. “It is a progressive autoimmune disease, and most of the time, patients will realize that they have this disease by seeing blood in their urine.”

A urine analysis would then detect protein in the urine. Aguiar-Lucander explained that it would take 10 to 15 years, and sometimes longer, for some of these patients to develop end-stage kidney disease. At this point, patients usually undergo dialysis, where water and toxins are removed from the blood as their kidneys won’t be able to perform this function anymore. Or, patients undergo kidney transplantation.

Calliditas’ TARPEYO gains full FDA approval

But that doesn’t mean that people have to wait until this stage to undergo therapy. There are treatments to slow the progression of IgA nephropathy. One of which is Calliditas’ TARPEYO, which was granted full approval by the U.S. Food and Drug Administration (FDA) to treat the disease, back in December.

TARPEYO has been developed to address the root cause of the disease cascade. While IgA nephropathy is a kidney disease, Aguiar-Lucander pointed out that it actually starts in the gut. In the end region of the small intestine called ileum, there is a cluster of immune cells called B cells called the Peyer’s patches. These cells produce the IgA protein, which is a normal function. But when these proteins are excessively produced or in the case of a leaky gut, these proteins enter the bloodstream, and eventually settle in the kidneys. 

The drug, which is a steroid, is delivered to the ileum, and then proceeds to down regulate B cell activity so that the production of IgA is controlled.

“This is the only drug that has this local targeted approach that is very disease specific,” said Aguiar-Lucander. 

Drugs called ACE inhibitors and angiotensin receptor blockers (ARBs) are regarded as the standard of care for IgA nephropathy. But these drugs only address high blood pressure in patients with the disease. While this is a major symptom that needs to be treated, it doesn’t target the high levels of protein in your urine called proteinuria. That’s where a drug like TARPEYO stands out.

The full approval came after the drug proved to have statistically significant benefit over the placebo. Patients who were given TARPEYO had 50% less deterioration of kidney function than those in the placebo group after two years of treatment. 

“I think this is a very big step forward for these patients. They’ve never really had anything that was specific. You want to try and do something for your patients, you want to try and keep them out of dialysis and transplantation. So there’s been very, very, little choice for doctors to do anything apart from blood pressure reduction, which has been shown in these clinical trials to not really be able to stop this kind of decline in kidney function,” said Aguiar-Lucander. 

“So, I think the full approval is a very significant, positive thing for patients, because now there is something that is specifically designed to address this disease, and has shown very good outcomes in clinical trials not just to reduce proteinuria, which is a symptom, but more importantly, to stabilize the kidney function during the time that the patients on this drug, and actually to preserve that benefit that was created during the treatment over time.”

Side effects of the drug are mostly local, although there is some spillover to the systemic circulation, according to Aguiar-Lucander. People tend to experience acne, minor increases in blood pressure, weight gain, and swelling.

TARPEYO paves way for IgA nephropathy new treatment options

TARPEYO’s clearance has spurred a slew of clinical trials for the condition. Aguiar-Lucander recounted that researchers at Calliditas worked with universities and regulators to figure out a way to create a regulatory path in order to run a pivotal trial for the rare disease, where one in 10 kidney biopsies in the U.S. show IgA nephropathy. Traditionally, the endpoints and the structure of the trials would require a very long time to study a drug. On top of that, the study would need many patients to participate, and for rare diseases, that’s not easy to have.

“There was a meta analysis that was conducted, that really looked at a variety of interventions into this patient group, and was able to really establish that there was a relationship between the reduction in proteinuria, and the underlying benefits in terms of kidney function. And so, on the basis of the meta analysis and our phase 2b data, which is a fairly large phase 2 trial with 150 patients, that was the basis for the FDA to agree to try to use this new endpoint reduction of proteinuria,” said Aguiar-Lucander. 

This can help the regulatory process to be smoother, particularly to attain accelerated approvals, whilst researchers wait for the long term data.

“I think that that really opened up a whole scope in the renal space. Investments in the renal space broadly have really increased, and it’s very much driven by this shift in regulatory pathway.”

Ongoing U.S. clinical trials for IgA nephropathy

At present, there are a number of clinical trials testing new treatments for IgA nephropathy. Multinational pharma Novartis’ iptacopan hit statistically significant proteinuria reduction with its drug iptacopan, which hinders the alternative complement pathway. The drug showed 38.3% reduction of protein buildup in the kidneys against placebo in a phase 3 trial. The study is set to end next year.

Moreover, Boston-based Alexion Pharmaceuticals’ monoclonal antibody ALXN1210, also known as ravulizumab is currently in a phase 2 trial. It is used to treat paroxysmal nocturnal haemoglobinuria, a rare condition where blood cells break apart and leads to to a low blood count and blood clotting. 

Another drug in the clinic is California-based Travere Therapeutics’ sparsentan, which received accelerated approval last year. It was the first drug to be greenlit by the FDA that did not suppress the immune system. It works by blocking pathways that contribute to the development of the disease, thereby turning down proteinuria in the kidneys.

The treatment is being evaluated in children with rare kidney diseases like IgA nephropathy as well as Alport syndrome, a genetic condition that damages blood vessels in the kidney, and IgA vasculitis, where IgA collects in blood vessels. However, a narrow miss in a recent pivotal trial threatens its approval.

One key biotech in the field is Canadian company Chinook Therapeutics, now owned by Novartis. Its drugs atrasentan and zigakibart are in the clinic. Atrasentan inhibits the endothelin A (ETA) receptor to decrease protein deposit, whereas zigakibart is a monoclonal antibody that blocks a cytokine involved in B-cell signaling. 

A phase 3 study for atrasentan that was completed last October, met its endpoint and was superior to placebo in proteinuria reduction, after 36 weeks. The final readout is expected in 2026.

Other drugs being tested in the U.S. include Vertex Pharmaceutical’s newly purchased povetacicept, which is another B cell cytokine antagonist, Visterra’s monoclonal antibody sibeprenlimab, and Vera Therapeutics’ atacicept that targets B cells.

Global clinical trials on the horizon for IgA nephropathy

Although the U.S. is at the forefront of these trials, IGNAZ, a study led by German biopharma MorphoSys is being conducted in a number of locations across the globe including the U.K., Spain, Germany, Australia, Japan, and Malaysia. The phase 2 trial is assessing the drug felzartamab against a placebo. The antibody, which was granted Breakthrough Therapy Designation for another kidney disease, recruits immune cells to kill B cells that play a role in how the disease manifests.

Meanwhile, a trial by Imperial College London in the U.K. for the tyrosine kinase inhibitor fostamatinib showed that it was able to tackle proteinuria by inhibiting the enzyme spleen tyrosine kinase. Plans to hold a larger, worldwide trial are in the works.

Despite recent flops like American biotechs Omeros dumping its monoclonal antibody narsoplimab, and Alnylam Pharmaceuticals narrowing its pipeline to exclude IgA nephropathy, scientists are coming up with more ways to treat patients in an effort to broaden treatment options. As a result, the standard of care seems to be evolving.

“I think that it’s really important for these patients to have an alternative now, which is designed for this disease, and also provides reduced kidney loss through this treatment,” said  Aguiar-Lucander. “We’re delighted to be pioneering this in this patient population. It’s an exciting time.”

Technologies related to IgA nephropathy treatment:

• target=”_blank” rel=”noopener”>NMR-based Metabolic Profiling of Rare Diseases – Imperial College London</span>