Idorsia’s Fabry flop puts focus on gene therapies

Fabry disease is caused by mutations in the GLA gene, which encodes the enzyme alpha-galactosidase A. This enzyme usually breaks down a fatty substance called globotriaosylceramide (Gb3), but in Fabry patients Gb3 builds up, causing symptoms such as pain crises, hearing loss and kidney and heart disease. The disease varies in severity depending on patients’ enzyme activity levels.

Replacing the enzyme is a mainstay of care, but the aforementioned issues mean that the search is still on for something better. Amicus’s Galafold, an oral drug designed to stabilise alpha-gal A, gained accelerated approved in 2018, but is only indicated for patients with certain GLA mutations.

Idorsia’s lucerastat, meanwhile, is an oral glucosylceramide synthase inhibitor designed to reduce Gb3 accumulation. Data from the Modify study suggest it does just that: Idorsia said yesterday that there was a “substantial and consistent reduction of plasma Gb3”; however, the trial did not meet its primary endpoint, reduction in neuropathic pain at six months, measured using the modified brief pain inventory-short form 3 score.

Jefferies analysts previously noted that this was an unusual endpoint, versus the more traditional Fabry outcomes of kidney or heart function, and this could provide a reason for the failure.

Idorsia does not seem to have thrown in the towel on lucerastat just yet. The group said more data, including results from an open-label extension study, would help inform a decision on the project’s future. But Jefferies says a path forward looks unlikely.

The Swiss group has other irons in the fire. It is expecting a US approval decision in the first quarter of next year on its insomnia project daridorexant, and data are due this quarter from a phase 2b trial of the sphingosine 1-phosphate receptor modulator cenerimod in systemic lupus erythematosus.

However, daridorexant’s pivotal data were mixed, and lupus is a notoriously tough nut to crack.

Gene therapies

If this is the end for lucerastat it will take out a project that had been expected to become the fifth-biggest seller in Fabry by 2026, according to Evaluate Pharma.

There is not much else on the near-term horizon. Protalix and Chiesi still hope for approval of PRX-102, which received an FDA complete response letter in April over manufacturing issues. However, this is merely a long-acting enzyme replacement therapy.

Sanofi’s venglustat completed a Fabry trial in 2016, but the group has yet to take the project further in the disease, despite still listing it in its pipeline. In any case this works similarly to lucerastat, so hopes cannot now be high.

This leaves a clutch of gene therapies, which all aim to deliver a working copy of the GLA gene and provide a once-and-done treatment. It is early days, but several are set to yield phase 1/2 data by the end of this year.

A number of gene therapy scares this year have raised the question about the safety of this approach more broadly – and raise the question of whether Fabry patients will want to go down this route given the availability of enzyme replacement therapies.

Perhaps things will have become clearer by the time the Fabry gene therapy assets have reached later-stage development but, until then, the biggest beneficiaries from lucerastat’s failure look like Amicus and the enzyme-replacement players.