Treatment Updates in Alport Syndrome

Alport syndrome is an inherited kidney disease characterized by abnormalities in the glomerular basement membrane and is associated with hearing loss, ocular anomalies, and risk for progressive loss of kidney function. Alport syndrome accounts for 3% of children with chronic kidney disease (CKD) and 0.2% of adults with kidney failure in the United States (1). The exact prevalence of Alport syndrome is unknown, but it is believed to be approximately 1 to 9 per 100,000 people (1). Alport syndrome is phenotypically heterogeneous and results from various patterns of genetic inheritance of mutations in type IV collagen genes (COL4A3, COL4A4, and COL4A5). The most common form is an X-linked mutation in COL4A5, which accounts for 80% of Alport syndrome. Inheritance may also be autosomal recessive and autosomal dominant. More rarely, Alport syndrome can be caused by de novo mutations in the collagen IV genes.

Although variable, the natural course of Alport syndrome progresses from hematuria to albuminuria, followed by proteinuria, glomerular and tubulointerstitial fibrosis, decline in estimated glomerular filtration rate (eGFR), and kidney failure. Current treatment recommendations for Alport syndrome focus on slowing this progression of kidney disease (Table 1).

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The current standard of care for patients with Alport syndrome includes the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). The recent Efficacy and Safety Study to Delay Renal Failure in Children with Alport Syndrome (Early PRO-TECT) trial demonstrated that early treatment with the ACE inhibitor ramipril reduced the albuminuria slope and delayed the decline in eGFR in children with Alport syndrome (2). In recent guidelines developed by Kashtan and Gross (3), genetic testing is recommended in suspected Alport syndrome patients with clinical or pedigree data suggesting a diagnosis of Alport syndrome to help guide treatment. In male X-linked and all patients with autosomal-recessive Alport syndrome, progression to CKD is more likely, and it is suggested that ACE inhibitor/ARB treatment begin at the time of diagnosis, unless diagnosis is before the ages of 12−24 months. Female X-linked and all autosomal-dominant patients are less likely to develop CKD; therefore, it is suggested that treatment with ACE inhibitors/ARBs should begin at the onset of microalbuminuria (3).

Several novel therapeutic agents for the treatment of Alport syndrome are currently being investigated. The Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome (CARDINAL) is a recently completed clinical trial that compared the efficacy and safety of bardoxolone methyl to placebo in patients with Alport syndrome and CKD. Bardoxolone methyl is an oral agent that activates transcription factor Nrf2 and inhibits nuclear factor-kB, thereby inducing anti-inflammatory molecular pathways, restoring mitochondrial function, and reducing oxidative stress. In a recent press release, Reata Pharmaceuticals announced positive results for the primary outcome, achieving a statistically significant improvement in eGFR of 7.7 mL/min/1.73 m² from baseline after 2 years in Alport syndrome patients with CKD treated with bardoxolone methyl compared to placebo (4). Additionally, Reata reported the results of the long-term extension trial, Extended Access Program for Bardoxolone Methyl in Patients with CKD (EAGLE), which also showed favorable outcomes with improvement in eGFR in 14 patients after 3 years of treatment (4). Bardoxolone was reported to be well tolerated, with muscle spasms and elevated aminotransferases observed as the most common adverse events. These data have not yet been peer reviewed or published. The company announced that it will be seeking US Food and Drug Administration (FDA) approval.

Additionally, the use of microRNA (miRNA)-based treatments has been of interest after clinical evidence of increased levels of miRNA-21 was determined to contribute to kidney fibrosis in Alport syndrome (5, 6). A phase 2 randomized, double blind, placebo-controlled study of lademirsen, an anti-miRNA-21 given by subcutaneous injection, is currently underway. The study, sponsored by Sanofi, has a target enrollment of 45 patients, and results are expected to be available in 2023 (7).

Atrasentan in Patients with Proteinuric Glomerular Diseases (AFFINITY) is a phase 2 open-label basket trial of atrasentan, an oral selective endothelin A receptor blocker agent. AFFINITY is set to begin recruitment in the first half of 2021. Chinook Therapeutics plans to recruit 80 participants with Alport syndrome, along with other proteinuric kidney diseases (8).

Overall, there have been many new developments in the diagnosis and treatment of Alport syndrome and promising clinical trials are underway. With these potential treatment options becoming available in the future, it is even more important that early diagnosis of Alport syndrome aided by genetic testing becomes more widely available and affordable. More research must be done to corroborate the guidelines regarding treatment paths for specific Alport syndrome genotypes. Last, with the recent increase in research for Alport syndrome, ongoing and upcoming trials should consider opinions of key stakeholders, including clinicians and patients, when planning clinical trials (9).