In late February, the US Food and Drug Administration (FDA) declined to grant marketing approval to the novel agent bardoxolone methyl as a treatment for Alport syndrome, which means this rare genetic disease that causes early onset progressive kidney dysfunction remains without a specific treatment.
Despite bardoxolone's rejection by the FDA because of what the agency said was inadequate evidence of efficacy for the first agent filed as a treatment for Alport syndrome, researchers and leaders from the Alport syndrome patient community see the experience as a small step forward in the effort to find effective interventions.
They believe the drug's development, testing, and regulatory submission blazed a path that previously did not exist for investigational Alport syndrome treatments and should aid development of future candidate treatments.
Bardoxolone's pivotal trial "demonstrated that it is possible to conduct an international clinical trial in Alport syndrome, and this could help with planning future studies," said Rachel Lennon, BMBS, PhD, professor of nephrology at the University of Manchester, UK.
"I am very optimistic about the prospects for new treatments for patients with Alport syndrome in the next 5 to 10 years," Lennon said in an interview.
"Having completed the first clinical trial...which was fully enrolled, and with other, available studies [now in progress] being filled with target numbers of patients with Alport syndrome, I believe our community has clearly demonstrated its motivation to change our outcomes and our families' stories by participating in research and in clinical trials," said Lisa Bonebrake, executive director of the Alport Syndrome Foundation, who also lives with the condition.
Although the FDA's decision "was not what we anticipated or hoped for" following the first pivotal trial in patients with Alport syndrome, "progress was still made," Bonebrake said in a statement on the FDA's decision.
The pivotal study, CARDINAL, randomized 157 patients with Alport syndrome to bardoxolone or placebo. The primary endpoint was change in estimated glomerular filtration rate (eGFR) from baseline after 48 and 104 weeks on treatment.
Bonebrake noted the study was "a catalyst for a new and more accessible genetic testing option that led to thousands of patients being accurately diagnosed and becoming aware of their specific genetic mutations." In addition, the trial and its follow-up, extended-access study, "proved that Alport syndrome patients are willing to participate in clinical trials," and that clinicians can now be "confident" in their ability to enroll "engaged patients." Bonebrake called this "a huge hurdle to overcome in a rare disease community."
FDA: The Evidence Did Not Prove Efficacy
The results of CARDINAL have not yet been published, but FDA staff summarized the findings in a briefing document the agency released when the advisory committee met in December 2021.
In that document, agency analysts conclude they "do not believe the submitted data demonstrate that bardoxolone is effective in slowing the loss of kidney function in patients with Alport syndrome and reducing the risk of progression to kidney failure." The advisory committee voted unanimously to not recommend the drug's approval. According to the committee's minutes, members cited low enrollment from the adolescent population, where more convincing outcomes may be possible, questionable efficacy, and safety concerns.
"I strongly support the FDA's decision," commented Lennon, who did not participate in the FDA review nor in the bardoxolone studies.
"The FDA, with the guidance of its advisory committee, made an informed decision based strictly on the scientific merits of the data," commented B. André Weinstock, PhD, who volunteers as research chair for the Alport Syndrome Foundation and is a member of the board of directors.
However, Weinstock, who has Alport syndrome, faulted what he said were "significant gaps in hearing patient voices" during the advisory committee meeting. As an example, he noted that the advisory committee appeared not to acknowledge nor consider a 2019 report on patient views on the development of drugs for Alport syndrome, "The Voice of the Patient," based on a 2018 meeting organized by the National Kidney Foundation and the Alport Syndrome Foundation. Weinstock was also lead author of a 2020 report from a workshop organized by the Alport Syndrome Foundation on appropriate designs of clinical trials.
Researchers also recently reported results from EAGLE, the extended-access study that followed CARDINAL, at the World Congress of Nephrology 2022. The follow-up included 114 patients at its start, including equal numbers who continued active treatment from the main study and those who crossed over to bardoxolone from the placebo group after CARDINAL ended.
According to Kandai Nozu, MD, professor and a pediatric nephrologist at Kobe University Graduate School of Medicine, Japan, EAGLE's findings showed preservation of kidney function for as long as 3 years on bardoxolone treatment concurrent with "mild" increases in urinary albumin levels. The most common adverse effect of treatment was muscle spasms, which occurred in about 30% of bardoxolone-treated patients.
Alport Syndrome Affects 60,000 Americans
Alport syndrome affects as many as 60,000 Americans and about 100,000 people in the European Union and is the second-most common genetic cause of kidney failure after polycystic kidney disease. Bardoxolone received an orphan drug designation from the FDA in 2017 as a treatment for Alport syndrome, a step that acknowledged the rarity of the condition but is independent of the FDA's decision to approve marketing of a new drug.
Alport syndrome is driven by mutations in the genes that produce the proteins that form type IV collagen. The defective collagen leads to disruptions in the collagen matrix, splitting within abnormal glomerular basement membranes, glomerulosclerosis with matrix deposition, and kidney fibrosis, among other things, causing progressive loss of kidney function and end-stage kidney disease early in life.
The abnormal collagen also occurs in the inner ear and eyes and often results in hearing loss and impaired vision.
Bardoxolone is a semisynthetic agent that activates nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that modulates expression of hundreds of genes involved in inflammation, oxidative stress, and cellular energy metabolism. Bardoxolone also suppresses production of proteins that mediate inflammation and production of reactive oxygen species.
The mechanism of action of bardoxolone, as well most other treatments being developed for Alport syndrome, moderates the adverse physiologic consequences of mutations that cause the syndrome rather than directly addressing the cause.
"Alport syndrome is a genetic disorder, and correcting a genetic defect is challenging," noted Lennon. The genetic malfunction results in "a complex cascade of events that ultimately lead to kidney failure." Determining how this cascade works and how it can be interrupted has slowed the development of effective interventions, she explained.
Development has also been hindered by limitations imposed by the low incidence of Alport syndrome. "The single most challenging obstacle in building a pipeline for Alport syndrome is that the disease is classified as rare," Bonebrake said in an interview.
Lack of a targeted therapy also dampens early diagnosis, noted Weinstock.
It "provides an excuse for uninformed clinicians that diagnosis of Alport syndrome is nothing more than consignment to dialysis and kidney transplantation," he said. "If we had an FDA-approved treatment, more attention would be paid to the condition and more resources devoted to ensure proper and early diagnosis."
Patients with Alport syndrome are commonly treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), an approach endorsed by guidelines published in 2013. However, these guidelines relied entirely on expert opinion, and these drugs do not have FDA labeling for Alport syndrome.
Plus, renin-angiotensin system (RAS) blockers "often come with challenging side effects," and "for some patients these drugs are not tolerated," said Bonebrake. However, Lennon sees value in using these agents, noting that RAS inhibitors "can extend kidney survival by more than 15 years" in some patients with Alport syndrome.
More Alport Syndrome Treatments Being Studied
New approaches to Alport syndrome research have recently appeared, as have more investigational interventions in clinical studies. Bonebrake cited an AS patient registry launched in 2021 as part of the NKF Patient Network by the National Kidney Foundation and the Alport Syndrome Foundation. And a University of Michigan study, NEPTUNE, has begun systematically collecting research specimens from patients with Alport syndrome.
Bonebrake also highlighted three new agents being studied in patients with Alport syndrome:
The HERA phase 2 study, sponsored by Sanofi, will enroll 43 patients with Alport syndrome to test the safety and efficacy of lademirsen.
Two "basket studies" are testing two investigational agents in patients with a variety of rare kidney disorders including Alport syndrome. The phase 2 AFFINITY study, sponsored by Chinook Therapeutics, is testing atrasentan in 80 adults with proteinuric glomerular disease that could be caused by Alport syndrome or any of three other conditions.
The phase 2 EPPIK study sponsored by Travere Therapeutics is testing sparsentan in about 57 children with proteinuric glomerular diseases caused by Alport syndrome or any of four other etiologies.
The three agents being studied in these trials have different mechanisms of action compared with bardoxolone, showing that the pipeline of novel interventions for patients with Alport syndrome "while still very small is starting to become more robust," said Weinstock.
"Credit must be given to Reata," the company developing bardoxolone, "and to their CARDINAL study for being first-to-file with the FDA for an Alport syndrome-specific therapy," Weinstock said in an interview. "The process will be smoother and easier for the Alport syndrome community the next time" a new drug seeks approval, he predicts.
CARDINAL and EAGLE were sponsored by Reata, the company developing bardoxolone. Lennon has reported being a consultant for Retrophin and Ono Pharmaceuticals. Nozu has reported receiving personal fees from Kyowa Kirin, a company that has licensed bardoxolone from Reata for development and marketing in Japan. Bonebrake and Weinstock have reported no relevant financial relationships.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler