ESGCT 2022 – Sangamo strengthens its case in Fabry

The group looks like the gene therapy contender to beat, but that is not saying much.

This time last year, four gene therapies were vying for a piece of the Fabry disease market. Since then, one has dropped out, one has disappointed and the chances for another look unclear – leaving Sangamo as the leader in this race.

The group strengthened its hand today with updated results from its phase 1/2 Staar trial of ST-920, including long-awaited data on patients not receiving enzyme-replacement therapy (ERT). However, it is probably too early to make a call on ST-920’s durability. And there are other projects in development designed to improve convenience over the current standard of care which, if successful, could provide competition.

Fabry disease, which is characterised by low levels of the enzyme alpha-galactosidase A (AGA), is already treated with ERTs such as Sanofi’s Fabrazyme. But patients need infusions every two weeks, and these therapies do not prevent disease progression.

Gene therapies are designed to correct mutations in the GLA gene that cause the disease, thereby providing a one-time cure and eliminating the need for ERT.

Sangamo has previously given updates from the Staar study, showing increased AGA levels after treatment with ST-920. These data were difficult to interpret given that most patients had continued to receive ERT.

At the European Society of Gene & Cell Therapy congress today the group presented data from nine patients, including four who have been weaned off ERT. Encouragingly, all four have maintained AGA levels above the normal range since ERT withdrawal. 

That said, the small number of patients involved, high variability in AGA levels between patients, and a relatively short follow-up time since withdrawal provide reasons for caution. And subject four has seen a steady decline in AGA levels, which could raise questions about durability.

Source: Company presentation

Sangamo is ahead of its Fabry disease gene therapy rivals. Avrobio discontinued development of AVR-RD-01, while Freeline disappointed with the first cohort from its Marvel-1 study of FLT190, as well as seeing myocarditis in both patients treated so far. Freeline recently started dosing a second, higher-dose cohort, and it will be worth keeping an eye out for this adverse event.

4D Molecular Therapeutics, whose 4D-310 once looked like the project to beat, recently expanded the eligibility criteria for its phase 1/2 study. At the time, SVB analysts called this move “confusing and inadvisable”, noting that it added unnecessary complexity given the variability among Fabry patients. 4D, which has reported data from three patients so far, expects to make another update in the first half of 2023.

Regulatory doubts

There are doubts about the FDA’s stance towards gene therapies in diseases that already have options, and the regulatory picture in Fabry was further complicated last year by the full approval of Fabrazyme, which had previously been available under accelerated approval.

This put an end to hopes that gene therapies could gain accelerated approval based on biomarkers. In addition to Avrobio’s exit, Amicus has backed away from gene therapies, including a Fabry candidate, with some scathing comments about its erstwhile rivals’ chances.  

For one, Fabry disease developers might now have to carry out pivotal trials against the likes of Fabrazyme. Sangamo says a phase 3 study is in the works.  

Others are also trying to develop options more convenient than ERT. Sanofi and Idorsia both have late-stage oral glucosylceramide synthase inhibitors, which are designed to reduce globotriaosylceramide (Gb3), the fatty substance that builds up in the disorder.

Still, the omens are not good for this class: in the phase 3 Modify trial, Idorsia’s lucerastat did decrease Gb3 levels, but failed on its primary endpoint, neuropathic pain. The company is persevering, pointing to renal and cardiac findings.

Sanofi is carrying out two phase 3 studies of its project venglustat in Fabry: Peridot versus placebo looking at pain, and Carat versus standard of care evaluating left ventricular mass index. Based on Idorsia’s experience, it might have a better chance in the latter.

The Fabry disease pipeline
Project Company Description Trial details/note
Pegunigalsidase Alfa Protalix Biotherapeutics/ Chiesi IV modified stabilised version of recombinant human α-galactosidase-A protein CRL Apr 2021 (manufacturing inspection), resubmission planned
Phase 3
Venglustat (GZ402671) Sanofi Oral glucosylceramide synthase inhibitor Peridot completes Nov 2024; Carat completes Jan 2025
Lucerastat Idorsia Oral glucosylceramide synthase inhibitor Modify failed Oct 2021; OLE continues
Phase 1/2
Isaralgagene civaparvovec (ST-920) Sangamo α-galactosidase gene therapy Preliminary data presented from Staar; ph3 planned
4D-310 4D Molecular α-galactosidase gene therapy Data presented from 3 pts in ph1/2; update due H1 2023 
FLT190 Freeline α-galactosidase gene therapy Data from 2pts in 1st cohort of Marvel-1 disappointed; dosing in 2nd cohort began Oct 2022
Phase 1
AL01211 Acelink Therapeutics Oral glucosylceramide synthase inhibitor Healthy volunteer study completed; ph2 in Fabry pts planned for 2023
Source: Evaluate Pharma &

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