As trial miss threatens FDA approval, Travere points to Filspari's benefits in bid to stay in kidney disease

Travere Therapeutics recently reported two pivotal trial flops for Filspari, with one threatening the drug’s accelerated approval in IgA nephropathy (IgAN) and the other raising doubts about its chances of tapping into another kidney disease.

More details from the two trials were shared at the American Society of Nephrology annual meeting on Friday. To hear Travere’s chief medical officer Jula Inrig, M.D., describe the situation, Filspari has shown consistent benefits in IgAN.

“All the ways we looked at it, we see patients on [Filspari] preserving more of their kidney function over the study period versus a maximally titrated active comparator, which is great for patients,” Inrig said in an interview.

The phase 3 PROTECT study compared Filspari with the traditional therapy irbesartan in IgAN. As Travere announced in September, the trial narrowly missed statistical significance on a secondary endpoint called estimated glomerular filtration rate (eGFR), which is designed to serve as confirmatory evidence for turning Filspari’s FDA accelerated approval into a full nod.

Compared with irbesartan, Filspari takers performed 1 mL/min better per year on the eGFR total slope endpoint, which measures patients' kidney function. Although the number missed statistical significance, it reached a range of improvement between 0.5-1 mL/min per year that’s generally thought to be clinically meaningful, Leerink Partners analysts said at the time.

On another secondary endpoint that serves as the confirmatory evidence for Filspari’s EU nod, the trial met statistical significance. When only data from week 6 were counted, Filspari showed a 1.1 mL/min per year advantage over irbesartan on the eGFR slope measure.

Further, Inrig called an absolute benefit of 3.7 mL/min for Filspari against irbesartan over two years as “a really meaningful” showing. Investigators also performed an analysis on a composite endpoint recording various signs of kidney failure, and Filspari did well there, too, according to the company.

“You can see that patients on the irbesartan arm start to reach the composite kidney failure endpoints sooner, and greater proportion of them reach it over time.”

The eGFR slope calculations didn’t count patients who stopped treatment early on. The results therefore favored irbesartan because it had a higher rate—1 in every 4 patients—of early discontinuations.

Data showed that treatment failure was a main reason for doctors and patients to stop their therapies early, Inrig said. If all randomized patients were counted, the trial would have hit statistical significance “with a meaningful separation” on the FDA confirmatory endpoint, she said.

Filspari got its IgAN nod in February and was the first non-immunosuppressive agent to win over the FDA. The accelerated approval was based on data from the same PROTECT trial showing Filspari was better at reducing proteinuria after 36 weeks of treatment.

Inrig declined to comment on Travere’s interactions with the FDA so far. Back in September, Travere said it plans to submit for full approval in the U.S. in the first half of 2024.

Meanwhile, Calliditas Therapeutics’ corticosteroid drug Tarpeyo is up for an FDA decision for a potential full-approval conversion in IgAN in December. The drug was tested against a placebo in a phase 3 trial. It would be difficult to compare that study with Filspari’s PROTECT because of different trial designs, baseline patient characteristics and eGFR calculation methodologies, Leerink analysts wrote in an October note.

Inrig said the outcome of Tarpeyo’s application won’t affect Filspari.

Besides IgAN, Travere also has the phase 3 DUPLEX trial for Filspari in the rare kidney disease focal segmental glomerulosclerosis (FSGS). That trial also failed to meet its eGFR slope primary endpoints.

At a 36-week interim analysis, a significantly higher rate of Filspari patients achieved partial remission compared to those who got irbesartan. The Travere drug also performed significantly better at proteinuria reduction. But those benefits didn’t translate into a big enough improvement in eGFR in a longer-term follow-up.

The annual eGFR slope, measured from day 1 to week 108, only showed a 0.3 mL/min benefit for Filspari versus irbesartan. When only counting the effect from week 6, the difference was wider at 0.9 mL/min.

Three main reasons could probably explain why Filspari’s proteinuria benefit didn’t translate into a longer eGFR improvement, Inrig said.

Filspari appeared to have a large, negative effect on eGFR at the beginning, which is “really hard to overcome in a two-year trial,” she said, especially when the treatment difference is expected to be just around 1 mL/min.

FSGS is a variable condition, making it even more difficult to reach statistical significance. Thirdly, both Filspari and irbesartan performed better than expected. So, Filspari would at least appear to have better results had it been compared with a placebo, Inrig said.

“Either way, we’re getting patients closer to normal,” she said.

As for whether a label expansion would be possible with the FDA based on the data, Inrig said Travere will “continue to figure out a path forward.”