A rare and life-threatening kidney disease in children finally has an effective therapy, thanks in large part to pioneering research and clinical leadership from University of Iowa Health Care Stead Family Children's Hospital.
The disease, known as C3 glomerulopathy (C3G), is an ultra-rare condition that primarily affects children and young adults. Only around 5,000 Americans have C3G, which causes progressive kidney damage, with more than half of patients reaching end-stage kidney failure within a decade of diagnosis.
Unlike previous treatments for C3G that aimed to alleviate the damaging inflammatory process of the disease, the new, first-of-its-kind drug directly targets the root cause of C3G dysfunction in the body's complement system, a part of the immune response.
Carla Nester, MD, director of the Rare Renal Disease Clinic at UI Health Care, led the global pediatric clinical trial for the new drug known as pegcetacoplan. The results were striking: there was a 68% reduction in the amount of protein in the patients' urine, and stabilization of kidney function. Up to 67% of children achieved complete remission, and 72% showed no disease activity on their kidney biopsies.
"This is the closest thing to a cure we've ever seen for this disease," says Nester, a professor of pediatrics with UI Health Care Stead Family Children's Hospital, who also is the senior author of the study, which was published in the New England Journal of Medicine on Dec. 3. "We still need to follow the long-term outcomes for these patients, but the data from this trial is absolutely amazing."
The phase 3, randomized, double-blind, placebo-controlled trial was conducted at 122 centers in 19 countries and included 124 patients. Based on the results, pegcetacoplan was approved earlier this year by the U.S. Food and Drug Administration (FDA) as the first treatment for patients 12 years and older with C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN), a closely related rare and severe kidney disease.
A global leader in rare kidney disease
Over that past several decades, UI Health Care has become a global leader in complement-mediated kidney diseases. This latest clinical advance is grounded in foundational research on the complement system led by Richard Smith, MD, UI professor of pediatrics and otolaryngology, and an expert in the causes of complement-related kidney diseases, and hearing loss. That research, combined with Nester's clinical expertise in the glomerular diseases, has made Iowa and the Stead Family Children's Hospital one of a very few centers in the U.S. capable of providing complete care to C3 Glomerulopathy patients, including efficient diagnosis, state-of-the-art management, and the opportunity to participate in both basic science and clinical research like the VALIANT trial, which tested pegcetacoplan.
"It's the combination of the research and the clinical unit that makes Iowa such a powerhouse," Nester says.
Importantly, the UI team has also earned the trust of patients and families affected by C3G, with patients traveling from across the country and around the world to seek care at the UI Rare Renal Disease Clinic.
"One of our patients used to fly in from Qatar to be seen in our clinic, and another moved from Europe to be under our care," Nester says. "That's how well known and trusted our program has become."
This strong reputation and connection with the patient community allowed UI Health Care to be the highest-enrolling center in this global study. Recruiting enough patients into these types of clinical trials for rare diseases is critical for demonstrating that a drug therapy is effective.
From bench to bedside — and beyond
The research done in Smith's lab over many years has advanced understanding of the underlying biology of C3G and led to a realization that inhibiting excessive activation of the complement pathway could be the key to an effective treatment. Determined to translate this knowledge into therapies for patients, the UI researchers collaborated with pharmaceutical companies to develop and test new drugs that could inhibit complement activation.
Unlike previous treatments, which relied on broad anti-inflammatory drugs like steroids, or medications that targeted the wrong aspect of the complement pathway,this new class of medication precisely blocks the malfunctioning part of the complement system.
Pegcetacoplan is administered via a twice-weekly injection, which many young patients prefer over daily oral medications. Another new drug called iptacopan, which also inhibits the complement system , was also approved earlier this year to treat adults with C3G. UI Health Care was the lead enroller globally for that clinical trial, as well, which led to iptacopan's approval.
For patients, the impact of these new medicines is profound. Nester recalls one college student who had been struggling with the disease and is now in full remission and thriving in his career, as well as pediatric patients who no longer have to worry constantly about their health and can instead look forward to normal childhoods.
"This is the year we finally get to help patients," Nester says. "It's been a long road, but we're here."
