Spotlight – Travere trips up but others are following in rare kidney disease

Travere’s attempt to win accelerated approval for Filspari in focal segmental glomerulosclerosis was rebuffed by the FDA in 2021, and the failure of the pivotal Duplex trial this week suggests that the agency was right to wait for more rigorous results. Not that the company is giving up on getting the drug to market in this use, with talks planned with regulators about potential ways forward.

Given the unmet need in this rare disease, and a fair amount of data that point in the right direction, Filspari should probably not be written off in FSGS just yet. But the Duplex outcome should give the handful of others working in this space food for thought, with the pipeline including projects from Vertex, Boehringer Ingelheim and Chinook.

Supportive sellside analysts pointed to the heterogeneous FSGS population as one potential reason for the failure of Duplex, a challenge that all developers will have to contend with. The disease manifests as scarring of certain areas of the kidney, although the speed that the fibrosis develops can vary widely.

Anything from 30-60% of people with FSGS progress to kidney failure, according to Travere. Others can see fibrosis resolve or experience a relapsing and remitting type of illness. The underlying cause of the disease is frequently not clear.

Filspari is a dual endothelin angiotensin receptor antagonist that works by reducing proteinuria – high levels of kidney-damaging protein in the urine – with the hope of preserving kidney function. The Duplex study compared sparsanten to Avapro, an off-patent angiotensin 2 antagonist sold by Sanofi for hypertension.

The trial failed on its two primary endpoints, which used separate measures of kidney function as assessed by eGFR, a measure of kidney function. Secondary measures, which included proteinuria and other renal endpoints, trended favourably, according to Travere, although whether regulators agree is now the big question.

Coming behind

So who might succeed in FSGS where Travere tripped up? The Australian group Dimerix looks to be most advanced, with the CCR2 antagonist DMX-200 already in phase 3. The first interim analysis of Action3 will take part in the second half of this year, assessing proteinuria reduction in the first 72 patients enrolled. This is the surrogate endpoint on which Travere tried and failed to win accelerated approval and, given the failure of Duplex, the relevance of hitting (or missing) this measure is questionable. 

In February Dimerix said the study had enrolled 96 subjects, out of a targeted 286.

DMX-200 appears to be the only CCR2 antagonist in development for FSGS, although Chemocentryx – which was bought by Amgen last year – was previously active here with the similarly acting CCX140. That project looks to have been abandoned before the Amgen takeout, however.

A higher-profile asset for investors is Chinook’s atrasentan, which is in a phase 2 trial in proteinuric glomerular disease study with FSGS cohorts, called Affinity. Data could emerge later this year, and Chinook is once again relying on change in proteinuria for its primary endpoint. 

Vertex’s work here is restricted to a genetic subtype of the already rare kidney disease, APOL1-medited disease. Overexpression of this gene can drive FSGS as well as other kidney diseases. An interim readout has been flagged as possible next year, otherwise investors will have to wait until 2026 for news on this project.

Lower on the radar are projects targeting transient receptor potential (TCP) channels, with work being undertaken by Boehringer Ingelheim and Goldfinch. The latter’s FSGS work ended earlier this year when the company was wound up. Its project, GFB-887, was sold to Karuna, which is taking it forward in mood and anxiety disorders.

Boehringer still lists its TRPC6 antagonist in its pipeline, although it has said little about it, and it is unclear whether this is distinct from another TRPC6 on which preclinical data were published a few years ago.

Neither are many details are available on R3R01, an asset currently in a small phase 2 trial with an FSGS subgroup, being run by the private group River Renal. The company was set up by Bain Capital and Narrow River Management, the latter of which specialises in buying in and developing big pharma castoffs. R3R01 has been described as a lipid modifying agent and its source is unclear.  

Other mid-stage works seems to have come to an end recently. Pfizer’s fusion protein PF-06730512 is listed on the group’s pipeline chart despite a phase 2 trial being terminated for efficacy in December, according to clinicaltrials.gov.

And it remains to be seen whether Acelyrin pushes on with VB119, an asset that was under development by Valenzabio, a company it acquired earlier this year. The project, described as a B-cell depleting mAb with potent binding to CD19, had been put through a small phase 2 trial with an FSGS subset. It is not currently mentioned in Acelyrin's pipeline. 

Early clinical work is under way at the sister Australian groups Occurx and Certa, which are moving forward with a couple of phase 1 assets, FT011 and OCX063. The former was for a while known as SHP627 and owned by Shire, but it was handed back when that group was bought by Takeda. OCX063 is moving into phase 2 this year, according to the companies’ websites.

Of this pipeline, Travere is still probably best placed to get a product to market first for FSGS, if it can win over the FDA with a totality of the data argument. But the Duplex result suggests that clinical work in FSGS needs much refinement, both in terms of finding relevant endpoints and careful patient selection.