Vertex finally catches a break

It has been a tough year or so for Vertex, so investors understandably reacted with relief today to news of a mid-stage win for the group’s beleaguered pipeline. Still, the data with VX-147, although promising, came in a genetic subtype of an already rare kidney disease, focal segmental glomerulosclerosis.

Much will depend on whether Vertex can prove VX-147’s worth in APOL1-mediated kidney disease more broadly – something the group hopes to show in its pivotal trial. Further upside could come if VX-147 can demonstrate utility in other kidney diseases such as lupus nephritis, and Vertex is investigating this possibility.

Proteinuria benefit

For now, though, the company at least has a win under its belt after several recent failures. The single-arm phase 2 study tested VX-147, an apolipoprotein L1 inhibitor, in 16 adults with FSGS and two APOL1 genetic variants. The project was given on top of standard of care, including Ace inhibitors, angiotensin II receptor blockers and steroids.

The primary endpoint was change from baseline in proteinuria, measured using the urine protein to creatinine ratio (UPCR) at week 13. In 13 evaluable patients, there was a 47.6% decrease. This looks impressive: Stifel analysts had set a bar of 30-40%.

True, three patients were excluded from the analysis because they were non-compliant with treatment, but Vertex’s chief executive, Reshma Kewalramani, noted during a conference call today that exclusion of such patients was part of its prespecified statistical analysis plan. In any case, including these patients did not change the results materially: she added that the mean reduction in proteinuria across all 16 subjects was 44%.

As for why these patients did not comply, Ms Kewalramani said this was not down to VX-147-related side effects; one patient, for example, had contracted Covid-19.

Indeed, VX-147’s safety profile looked good, with no serious adverse events deemed related to the project, and no discontinuations due to adverse events.

Accelerated approval?

A big question now is whether Vertex will be able to use proteinuria as a surrogate endpoint for accelerated approval. This is the group’s current plan, although it still needs to have an end of phase 2 meeting with the FDA to nail down the details of its pivotal trial.

Ms Kewalramani noted several times that reductions in proteinuria are associated with improvements in the harder endpoint of estimated glomerular filtration rate, and that regulators are becoming increasingly comfortable with the proteinuria endpoint.

Still, the FDA recently knocked back Travere Therapeutics’ plan to use proteinuria data to file for accelerated approval of sparsentan in FSGS. That group now plans to file in mid-2022 with eGFR data in hand. Travere is investigating sparsentan in FSGS more broadly, rather than focusing on the APOL1 subtype as Vertex is.

Around 40,000 people in the US have FSGS. Vertex estimates that APOL1-mediated kidney diseases more broadly affect 100,000 people in the US and Europe, though it reckons this is an underestimate given the lack of options for the disease.