Povetacicept, an experimental drug for a rare kidney disease called IgA nephropathy (IgAN), has been declared a “breakthrough therapy” by the FDA. This status is given only to drugs that may treat a serious condition and whose early test data shows that they could work better than other therapies that are already available.
Being declared a “breakthrough therapy” means that povetacicept is being developed and reviewed for FDA approval faster than other drugs.
“[It’s] a very promising and exciting treatment option for patients with IgA nephropathy,” says Mayurkumar Patel, MD, a nephrologist and associate program director of nephrology fellowship at Jersey Shore University Medical Center in Neptune, New Jersey. “It works differently and potentially better than traditional treatments by targeting the root cause of IgA nephropathy rather than managing its downstream damage.”
Every drug that’s approved by the FDA goes through a lengthy and rigorous process to prove that it’s safe and effective. That includes lab research, testing by volunteers, and review of data by doctors and scientists. Here’s a look at the steps that povetacicept researchers took to earn FDA approval.
Step 1: Understanding the Disease
Before scientists can look for a new drug, they need to understand as much as they can about the disease they want to treat.
IgAN (Berger’s disease) happens when antibodies (immunoglobin A) that your immune system makes to fight germs clump up in your kidneys instead. Over time, that can cause inflammation, damage, and kidney failure.
Your kidneys filter toxins and waste from your body. When they don’t function well, protein will show up in your urine (proteinuria). IgAN can also cause blood to leak into your urine (hematuria), high cholesterol, high blood pressure, swelling, and heart disease.
Scientists still don’t understand why some people get IgAN. Your genes and environment (things that you’re exposed to) both appear to play a part.
IgAN doesn’t have a cure. Treatments usually focus on managing your symptoms and trying to slow how quickly your condition advances. Experts keep looking for new IgAN therapies that can help more.
Step 2: Identifying a Promising Target
Once researchers understand how a disease unfolds inside your body, they can look for a weak or vulnerable part of the process and think about chemicals, genes, or proteins that may be able to target it.
Povetacicept is a newer type of drug called a dual BAFF/APRIL inhibitor. BAFF and APRIL are cytokines, chemicals that help your immune system. They’re involved with the life cycle of B cells, which are white blood cells that make antibodies.
“We actually know that BAFF and APRIL levels are elevated in people living with IgAN, as well as other immune-mediated diseases,” says Manish Maski, MD, a board-certified nephrologist and executive director of medical affairs at Vertex, the company that makes povetacicept.
Vertex researchers believed that targeting both BAFF and APRIL could treat IgAN by helping to bring B cells under control.
“The key question was, ‘Can we build a more effective dual BAFF/APRIL inhibitor?’” Maski says. “Povetacicept was engineered to bind very tightly to both BAFF and APRIL, and the hope is that if we can potently modulate the levels of both BAFF and APRIL, we give patients the best chance at modifying the trajectory of their disease.”
Step 3: Further Testing in a Lab
As soon as researchers believe that they’ve found a promising treatment, they do preclinical studies (lab and/or animal testing) to get a better idea of how well it could work in humans and any harm that it may cause.
In early testing, Vertex researchers compared povetacicept to other APRIL, BAFF, and dual BAFF/APRIL inhibitors. They looked at its:
- Binding affinity (how well it binds to BAFF and APRIL pathways)
- Potency (the amount needed to be effective)
- Tissue distribution (where it goes in the body)
- Pharmacokinetics (how it’s processed by the body over time)
“Perhaps the most convincing evidence came from lupus models,” Maski says. “In lupus-prone mice, povetacicept reduced autoantibody levels, decreased proteinuria, improved kidney pathology, and extended survival.”
The results from these early studies gave Vertex researchers the confidence to test povetacicept in people who live with IgAN.
Step 4: Clinical Trials in People
Clinical trials enlist volunteers to try new treatments and confirm how well they work. Every investigative drug has to go through different types of clinical trials to get FDA approval. These include:
Phase 1 trials
- Include 20-100 people
- Last several months
- Focus on safety and dosage
Phase 2 trials
- May include several hundred people
- Could last up to two years
- Focus on how effective the drug is and any side effects it causes
Phase 3 trials
- Enroll between 300 and 3,000 people
- Last one to four years
- Test how well the drug works and keep tabs on any adverse reactions
Povetacicept’s clinical trials included:
RUBY-3 trial
This phase 1/2 study enrolled 21 people with IgAN, who received 80 milligrams of povetacicept in a shot every four weeks.
Seventeen people continued taking it for 48 weeks. Among the results at that time:
- 64% decrease in protein in participants’ urine
- 90% of participants had less or no blood in their urine
- 53% of participants achieved clinical remission
The FDA granted povetacicept "breakthrough therapy” status for IgAN because of data from the phase 2 RUBY-3 clinical trial.
RAINIER trial
This phase 3 randomized, double-blind, placebo-controlled trial took place around the world and included 605 volunteers with IgAN. Every four weeks, some were given 80 milligrams of povetacicept while others received a placebo (a harmless substance with no medicine in it).
By week 36, researchers noted significant improvements in people who were treated with povetacicept, including:
- 52% reduction of protein in urine
- 77.4% reduction in Gd-IgA1, a biomarker linked to IgAN
- 85.1% no longer had blood in their urine
How safe is povetacicept?
During the RUBY trial, researchers found that povetacicept was well-tolerated. Most of the reported side effects were mild, and none led volunteers to switch to a lower dose or drop out of the study.
Based on data that was collected during RAINIER’s 36th week, researchers confirmed that povetacicept was generally safe.
“Most adverse events were mild to moderate, mainly upper respiratory infections and injection site reactions,” Patel says.
No one dropped out of the trial due to infections.
There were no serious adverse events (SAEs) related to povetacicept and no deaths in the trial.
Step 5: FDA Review and Monitoring
Based on the strength of the RAINIER trial results, the makers of povetacicept submitted a Biologics License Application to the FDA. Scientists and doctors are now carefully reviewing povetacicept’s data. Their decision is expected in November. If povetacicept’s application is accepted, doctors will be able to prescribe it as an IgAN treatment in the U.S.
As with all new drugs, researchers will continue to learn more about povetacicept and keep monitoring the people who took part in the clinical trials.
“Following the potential FDA accelerated approval, patients will continue in RAINIER as the study continues in a blinded manner until the last patient completes 104 weeks,” says Maski.
People who reach week 104 will also have an option to enroll in another extension study and receive another 104 weeks of treatment and follow-up.
Step 6: New Hope for Treating IgAN
Up to 30% of people with IgAN develop kidney failure within 20 years of diagnosis, so more effective treatment options are needed. Recently, six new drugs received FDA indications for IgAN. Povetacicept is widely expected to become the seventh. In the meantime, researchers are already holding clinical trials to see which other autoimmune conditions povetacicept may be able to treat.