Sparsentan Approval Marks Historic Milestone for FSGS Treatment: Kirk Campbell, MD

Last month, the FDA approved sparsentan (Filspari; Travere Therapeutics) to reduce proteinuria in patients 8 years and older with focal segmental glomerulosclerosis (FSGS) without nephrotic syndrome, a rare kidney disorder that can often lead to kidney failure.

Kirk Campbell, MD, chief of the renal division at the University of Pennsylvania and president of the National Kidney Foundation, recently spoke with The American Journal of Managed Care^® (AJMC^®) about the significance of the decision, which marked the first approved therapy for this condition.

He discussed the longstanding challenges of treating FSGS without nephrotic syndrome, describing sparsentan’s approval as a major milestone. Campbell also addressed key safety and monitoring considerations, as well as the importance of long-term real-world evidence and patient access as the therapy enters clinical practice.

Watch the interview here.

This transcript has been lightly edited for clarity.

AJMC: Why has FSGS without nephrotic syndrome historically been so difficult to treat?

Campbell: FSGS isn't really a disease but a histologic pattern of injury where there's patchy scarring affecting the kidney filter. We have a number of different underlying etiologies for FSGS, including 60-plus gene mutations, immunologic causes, obesity-related disease; there are gene modifiers and medications. So, classifying and defining the condition has been one reason that we have not been able to effectively manage it over the years.

The other part of it is that we didn't have good end points right for clinical trials and patient monitoring activities, so that's changed a lot, especially as we've understood a lot more about disease pathogenesis. A number of advances in the field have really converged upon this moment, where we now have better options for a condition that we understand a lot better.

AJMC: The FDA recently approved sparsentan to reduce proteinuria in patients aged 8 and older with FSGS without nephrotic syndrome, marking the first approved therapy for this condition. How significant is this milestone, and what impact could it have on patients and clinical practice?

Campbell: This is a very significant moment. This is the first-ever approved therapy for FSGS. Again, even though it's a heterogeneous condition, it's the beginning, we hope, of a journey that will really bring a lot more treatment options that are safer and more efficacious than what we currently have available.

This is also the first time the FDA has approved an agent on the basis of reducing proteinuria, marking another effective milestone, where the reduction of proteinuria is now being recognized as a validated therapeutic end point for approvals in this space.

AJMC: Sparsentan is classified as both an angiotensin II receptor blocker and an endothelin-1 receptor antagonist. Why might targeting both pathways simultaneously be more effective than targeting either alone in FSGS?

Campbell: Angiotensin II acts through AT1 receptors, and that drives intraglomerular hypertension and really increases pressure on certain types of kidney cells and the kidney filter. It can also have an impact on scarring. We know that angiotensin receptor blockers, ACE inhibitors, for years, have been used to treat protein-spilling kidney conditions.

Endothelin-1 acts through the ETA receptor, and we've been learning a lot more about how endothelin-1 can cause injury to kidney podocytes, mesangial cells, and also scarring and inflammation in the tubulointerstitial compartment of the kidney.

So, it makes sense that targeting both of these mediators of kidney injury together in one treatment approach would be a strategy that's useful. We are seeing a lot of agents being developed that are targeting endothelin-1 across protein-spilling kidney conditions.

AJMC: What should clinicians know about the safety and tolerability of this regimen?

Campbell: The FDA approved sparsentan on the basis of it being effective in reducing proteinuria and also having a benefit on kidney function, but also the safety was evaluated; that's an essential component. Clinicians, however, do need to be, and patients as well, aware of some monitoring that needs to occur.

So, patients need to have their liver enzymes and bilirubin levels monitored before and then checked every 3 months while on treatment because of the theoretical risk of hepatotoxicity. We didn't see increased risk of liver injury in the pivotal phase 3 study, but still, that requires monitoring while patients are on this drug.

We also know that this drug is contraindicated in pregnancy, so pregnancy precautions are needed. Beyond that, some of the more commonly reported adverse effects would include some edema, or peripheral edema; blood pressure can become lower; and potassium levels can be higher, as well as anemia. Again, these should be monitored with agents in this class.

AJMC: Looking ahead, what will you be watching most closely as sparsentan moves from clinical trials into everyday practice?

Campbell: We'll want to see how this treatment approach works in the real world. Clinical trial results are encouraging, and they're important for initial drug approval, but we really want real-world evidence of long-term effectiveness and safety over many, many years that patients will need to take this drug, and in combination, likely, with other agents to reduce proteinuria and stabilize kidney function.

We'll also want to see who responds best. As mentioned, FSGS is a very heterogeneous condition, so there are a number of subgroups that we're going to pay a lot of close attention to: patients who have these genetic underpinnings or immunologic underpinnings or various secondary causes of kidney injury that can be manifested as this FSGS lesion.

We also want to make sure that patients get full access to treatment options such as this when they would benefit the most, because approval doesn't always translate into full implementation and uptake, so that'll be something we'll watch very closely. The other part of it is the impact on the pipeline of drug development in the FSGS space. We are seeing an increase in clinical trial activity, and so hopefully we'll see a lot more treatment options becoming available for patients with FSGS in the future.