Substrate reduction therapy for Fabry disease

Last updated May 31, 2024, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

Substrate reduction therapy is an investigational treatment strategy that’s being explored as a way to reduce the toxic accumulation of fatty substances in people with Fabry disease.

Due to mutations in the GLA gene, people with this rare disease have either a reduced activity or a complete absence of the alpha-galactosidase A (alpha-Gal A) enzyme, whose primary function is to break down certain fatty molecules into building blocks that cells can use.

The main substrate of alpha-Gal A, or the molecule it’s intended to bind and metabolize, is globotriaosylceramide (Gb3). As such, people with Fabry experience a toxic accumulation of Gb3 inside cells, which ultimately causes damage to the body’s tissues and organs.

Currently, approved Fabry disease treatments all focus on increasing the amount of functional alpha-Gal A that’s available to degrade Gb3 and other fatty substances. However, substrate reduction therapies work by inhibiting an enzyme involved in the production of those molecules, lowering Gb3 levels through a mechanism that’s independent of alpha-Gal A.

What is substrate reduction therapy (SRT)?

Substrate reduction therapy, or SRT, is a strategy designed to reduce the production or accumulation of harmful substances in the body. It has been explored mainly for treating lysosomal storage disorders such as Fabry.

Lysosomes are cellular compartments that function as the cells’ disposal systems for molecular garbage, working to degrade unneeded or faulty molecules into smaller components that can be recycled by cells. In lysosomal storage disorders, one or more lysosomal enzymes are absent or defective, leading waste molecules to build up to toxic levels inside cells.

The main aim of substrate reduction therapy, as the name suggests, is to reduce the production of the faulty enzyme’s substrate. By limiting the amount of substrate available for storage, the approach helps to slow or stop the toxic buildup that drives disease progression.

However, because lysosomal storage disorders are caused by deficiencies in distinct enzymes leading to the accumulation of different substrates, there isn’t a one-size-fits-all substrate reduction therapy.

In Fabry, SRTs currently in development are designed to block an enzyme called glucosylceramide synthase, which is involved in the production of complex glycosphingolipids, a group of molecules that includes Gb3. By inhibiting that enzyme’s activity, these therapies reduce the amount of Gb3 and other fatty substances that are produced in the first place.

Because this mechanism is independent of whether alpha-Gal A is deficient or missing, it offers a potential alternative strategy that is not limited to people with specific GLA mutations, as is the case with an approved treatment option called chaperone therapy.

Potential benefits of SRT for people with Fabry disease

SRT has the potential to slow the progression of symptoms and limit disease-related organ damage in people living with Fabry disease.

So far, data from clinical trials in Fabry patients have shown the benefits of substrate reduction therapy, including a reduction in Gb3 levels in the blood and skin cells, as well as stabilization of disease progression in the kidneys, heart, brain, and nervous system.

One notable advantage of SRT is its mode of administration: it can be taken orally, which is generally more convenient and less invasive than approved enzyme replacement therapies (ERT), which require routine infusions into the bloodstream.

Additionally, SRT has the potential to cross the blood-brain barrier — a semipermeable membrane that protects the brain and spinal cord from molecules circulating in the bloodstream. This means that substrate reduction therapies may help address the disease’s neurological symptoms, which are not effectively managed with ERT due to its limited ability to penetrate this barrier.

Still, SRT may not be sufficient as a standalone treatment for patients with minimal to no residual alpha-Gal A enzyme activity, who may benefit from a combination of both SRT and ERT. The dual approach may help address the limitations of each individual therapy, offering a more comprehensive and effective strategy for managing Fabry disease.

In other diseases, SRT has proven beneficial for a lysosomal storage disorder called Gaucher disease, for which two oral SRT medications are already approved and offer an alternative to enzyme replacement therapy. The approach is being investigated as a potential standalone or combination therapy for many other lysosomal storage disorders.

SRT in clinical development

Three SRTs are currently being tested in clinical trials for Fabry disease: venglustat, lucerastat, and AL01211. All are designed to lower Gb3 levels and ease Fabry disease symptoms by inhibiting the glucosylceramide synthase enzyme.

Venglustat

Venglustat, which is being developed by Sanofi for Fabry and other diseases, was first tested in 11 men with Fabry who took part in a Phase 2a clinical trial (NCT02228460). The therapy was administered as a once-daily oral capsule for six months, after which some participants continued to receive the medication for a total of up to three years in the trial’s extension study (NCT02489344).

While the therapy did not significantly reduce Gb3 accumulation in skin cells after six months — failing the trial’s main goal — most patients who remained in the extension trial did experience a reduction in Gb3 buildup after three years of treatment. These patients also had no signs of clinical disease progression in the kidneys, heart, brain, or nervous system after three years. Most side effects were mild and not related to venglustat.

Two Phase 3 clinical trials called PERIDOT study (NCT05206773) and CARAT (NCT05280548) are now evaluating whether venglustat can ease certain disease symptoms, including nerve pain and heart disease.

Lucerastat

Lucerastat, an experimental oral SRT being developed by Idorsia, was able to reduce Gb3 blood levels by nearly 50% in a group of 118 adults with Fabry disease who participated in a Phase 3 trial (NCT03425539).

Named MODIFY, the trial tested the therapy against a placebo, both given as hard gelatin capsules twice daily, for six months. The main goal was to see if the therapy was more effective than a placebo at easing neuropathic pain, or pain related to nerve damage.

While that goal was not met, some patients who received up to two years of lucerastat treatment in MODIFY and its open-label extension study (NCT03737214) experienced slower declines in kidney function and improvements in measures of cardiac health. The therapy was well tolerated, and no patients experienced serious side effects related to it.

The extension study is ongoing and will treat patients for up to four years to test whether long-term lucerastat can limit damage to the kidneys and/or heart.

AL1211

AL1211, a newer oral SRT being developed by AceLink Therapeutics, has so far been able to reduce levels of Gb3 and related fatty molecules, as designed, in healthy volunteers who took part in a Phase 1 trial (NCT04908462).

A Phase 2 clinical trial (NCT06114329) is ongoing to test its safety and preliminary signs of efficacy in about 18 previously untreated men with classic Fabry disease, a more severe form of the disease that manifests in childhood or adolescence.

Risks and side effects

Available data from clinical trials of SRTs currently in development for Fabry indicate that the most common side effects of substrate reduction therapy may include:

• hot flushes
• flatulence
• depressed mood
• shortness of breath
• dizziness
• nausea.

Other side effects that may be related to substrate reduction therapy use in Fabry disease patients include:

• vertigo
• low sodium levels
• bladder inflammation
• respiratory tract infection
• nausea and fatigue
• dry skin
• postmenopausal bleeding.

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