Fabry disease (FD) is a rare disease lysosomal storage disease resulting from a mutation in the galactosidase-α (GLA) gene, which encodes the lysosomal enzyme α-GAL A. This mutation leads to the accumulation of globotriaosylceramide (Gb3), a toxic metabolite.

The current treatment for FD involves the use of enzyme replacement therapies (ERTs), whereby patients are given intravenous α-GAL A enzyme, leading to a reduction of Gb3 levels in the blood. There are currently three ERTs available in this space, namely Sanofi Genzyme’s Fabrazyme (agalsidase beta), Shire’s Replagal (agalsidase alfa) and JCR Pharmaceuticals’ biosimilar agalsidase beta. Fabrazyme is available in both the US and Japan, while Replagal and JCR’s therapy are both only available in Japan.

Since 2018, Amicus Therapeutics’ Galafold (migalastat hydrochloride), a novel oral pharmacological chaperone therapy, has also been available for the treatment of FD. Galafold is an orally administered therapy that prevents the accumulation of Gb3, is available in both the US and Japan, and is often prescribed for late-onset FD patients. Galafold has been the most recent therapy to enter the FD market in the last 15 years, stealing market share from the incumbent ERTs and beginning to address the unmet needs for FD therapies with novel mechanisms of action (MoAs), improved efficacy and improved patient compliance.

The FD pipeline has two therapies in late-stage development. These are Chiesi Farmaceutici’s pegunigalsidase alfa, an ERT in pre-registration in the US, and Idorsia Pharmaceutical’s lucerastat, an oral glucosylceramide synthase (GCS) inhibitor in Phase III in the US and Japan. The overall clinical data from both of these therapies, however, remains inconclusive. Key opinion leaders interviewed by GlobalData reported that they remain unconvinced of the efficacy and primary endpoints of the trials for these therapies.

In a direct head-to-head comparison with Fabrazyme, pegunigalsidase alfa has not demonstrated a very significant improvement in efficacy. Pegunigalsidase alfa’s clinical data, however, has demonstrated some significant benefits as it requires a decreased frequency of administration (once a month compared to bimonthly administration with existing ERTs) and shows improved drug clearance, as observed in the head-to-head trial with Fabrazyme.

Oral therapies such as lucerastat and marketed Galafold offer novel MoAs that provide support to enzymes in the GLA-α metabolic pathway to prevent the accumulation of Gb3. As a pharmacological chaperone, Galafold stabilises the mutant α-GAL A, increases intralysosomal levels and restores intralysosomal activity. Lucerastat inhibits the GCS enzyme, which is the first step of the glucosylceramide biosynthetic pathway, and prevents the accumulation of Gb3. These two therapies and their novel MoAs offer a therapeutic regimen with improved efficacy for mild FD adult patients that will steadily eat away at the market share held by incumbent ERTs.

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The Figure below represents sales for the FD market.

GlobalData expects the FD market to see significant growth from 2020 to 2030. The two major markets (2MM), namely the US and Japan, will increase from total sales of $820.15m in 2020 to $985.81m in 2030, at a compound annual growth rate (CAGR) of 1.9%. This sales growth will be in line with a steadily increasing disease prevalence and the entrance of novel agents into the market. Several drugs in the pipeline have novel MoAs, including gene therapies that offer the promise of single-dose and potentially curative therapies.

Several gene therapies currently in Phase I or II are expected to enter the US FD market from 2026 onwards. These therapies are designed to consist of a single dose and are potentially curative, with data from up to 22 months post-dose demonstrating sustained levels of α-GAL A or a sustained reduction in Gb3. Two of these therapies, 4D-310 and ST-920, are adeno-variant-based vector therapies. The third, AVR-RD-01, is a lentiviral vector-based therapy.

Each of these gene therapies is at a similar stage of development, and AVR-RD-01 has clinical data demonstrating long-term efficacy for up to 22 months. These therapies will capture a small share of the FD market, as physicians are only likely to prescribe them for early-onset FD patients who are unresponsive to ERT or when the cost-to-benefit ratio favours gene therapy over ERT, potentially with paediatric patients. Clinical data for ages younger than 18 years, however, remains to be determined.

In addition to late-stage pipeline agents, another driver of market growth for FD will be an increasing number of early diagnoses. Across the 2MM, regions are driving to increase screening rates for newborns, infants and paediatric patients who demonstrate the early neuromuscular, cardiac and digestive system complications that are associated with FD. This will increase the number of prescriptions for ERTs and possibly also for gene therapies for paediatric patients.

Paediatric cases will, however, only remain a small fraction of the patient share in the FD market, as not all regions are likely to adopt neonatal screenings and FD symptoms often do not present until adulthood. One significant barrier to the growth of the FD market will be the cost of therapies. This challenge will remain with novel therapies, particularly gene therapies.