The FDA has approved Filspari (sparsentan) for focal segmental glomerulosclerosis (FSGS), a rare kidney disease caused by mutations in INF2, the same gene linked to CMT dominant intermediate E (CMTDIE). This is the first approved treatment specifically for this kidney disease it represents a treatment option that has not previously existed.
One gene, two diseases
CMTDIE is caused by mutations in the INF2 gene. This gene encodes the INF2 protein that regulates cell shape and stability in peripheral nerve cells. Disrupted INF2 impairs the cytoskeleton, the internal scaffolding that keeps nerve fibers structurally intact. The resulting damage accumulates over time, leading to the muscle weakness and sensory loss that define CMT for people living with this subtype.
In kidney cells, mutations in INF2 disrupt the structure of podocytes, specialized cells that form part of the kidney’s filtration system. When podocytes fail, protein leaks into the urine, a condition called proteinuria (excess protein in the urine, a marker that the kidneys are not filtering correctly). Left unaddressed, this progresses to focal segmental glomerulosclerosis, or FSGS, specifically a subtype called FSGS-5. Not every person with CMTDIE develops FSGS, but for those who do, the disease can advance to dialysis or kidney transplant without effective treatment.
Because these two diseases share a genetic root, clinicians who care for people with CMTDIE monitor kidney function as part of standard care. FSGS usually presents with proteinuria, which can prompt referral to a nephrologist, a physician who specializes in kidney disease, for closer assessment. Proteinuria is when the kidneys release an extremely high level of protein into the urine.
What is Filspari?
Travere Therapeutics received full FDA approval for Filspari (FILL-spare-ee), a dual-acting medicine that blocks two molecular pathways known to drive kidney damage in FSGS. According to the company, Filspari is the first drug the FDA has approved specifically for FSGS. Filspari is approved to reduce proteinuria in adults and children ages 8 and older with FSGS who do not have nephrotic syndrome.
The company reported that Filspari works by blocking the endothelin A receptor and the angiotensin II receptor, two signaling pathways that, when overactive, accelerate the scarring and protein leakage that characterize FSGS. According to the company, this dual-blockade mechanism differentiates it from earlier single-pathway treatments and is the basis for the FDA’s approval.
Although the clinical trial did not meet its original primary endpoint, which is a fairly common occurrence in rare disease trials, the patient advocacy group NephCure worked with Travere Therapeutics and the FDA to revise the primary endpoints. The collaboration ultimately helped bring the first FDA-approved treatment for FSGS to patients and demonstrates the important role patient advocacy group-industry partnerships can play in rare disease drug development.
What this means for people with CMTDIE
For people with CMTDIE who also have FSGS-5, the approval changes the treatment landscape. Until now, there has been no FDA-approved treatment for FSGS. Physicians and patients have had to rely on supportive care. The availability of an approved drug specifically for FSGS gives healthcare providers a new option to discuss with their patients. For people with CMTDIE who do not have FSGS, this has not been studied in peripheral nerve function and has not been approved to treat neuropathy of any kind, including CMT.
Read Travere Therapeutics’ full announcement for additional details.
Sue Bruhn, PhD, CMTA CEO, is a member of the Travere Therapeutics Board of Directors.
