About Troriluzole
- Márcio
- Dec 14, 2024
- 5 min read
NAF webinar - Dr. Susan Pearlman
Comments by Márcio Galvão (ABAHE volunteer)
Context (notes by Márcio Galvão)
Purkinje cells (PCs) are important inhibitory neurons in the cerebellum. They use the neurotransmitter GABA (gamma-aminobutyric acid) to inhibit the activity of other cerebellar neurons. However, the PCs receive excitatory signals from other neurons (parallel fibers originating from granule cells), and this signaling uses the neurotransmitter glutamate. This helps modulate the electrical activity of the PCs, which is important for our motor coordination. Thus, although the PCs inhibit other neurons, they themselves are excited when they receive glutamate, which is important for their functions in controlling our movements.
The problem is that EXCESS GLUTAMATE is harmful to neurons. It can cause EXCESSIVE STIMULATION, which is toxic and results in neuron death. As we've seen, Purkinje cells inhibit the activity of several other neurons. If they die, an uncontrolled increase in the activity of these other neurons can occur, which is not good.
This isn't just the cerebellum. This "neuronal poisoning from excess glutamate" can occur in various parts of the brain and is associated with various types of neurological diseases:
- Huntington's disease
- Alzheimer's disease
- Amyotrophic lateral sclerosis (ALS)
- SPINOCEREBELLAR ATAXIAS (SCAs)
IN OTHER WORDS - Very high glutamate levels can cause neuronal death in several regions of the brain, and when the cerebellum is affected, symptoms of ATAXIA may appear (too much glutamate stimulation -> too much calcium enters the cell -> causes mitochondrial dysfunction and activation of enzymes that degrade the cell, oxidative stress and death of Purkinje cells).
What can cause this excess glutamate?
- Reduction in the reuptake (reuse) of glutamate by astrocytes (glutamate - glutamine)
- Conditions that cause excess glutamate release (e.g. stroke, oxidative stress, metabolic problems, etc.)
Is Ataxia a cause or consequence of excess glutamate?
It can be one or the other, depending on the subtype and the mechanism involved.
ATAXIA AS CAUSE: Genetic mutations in glutamate receptors, deficiency in glutamate reuptake (reuse), etc.
ATAXIA AS A CONSEQUENCE: Neuron death (from other causes) can lead to glutamate accumulation. In this scenario, excess glutamate is not the primary cause of ataxia, but a side effect of ataxia itself, which can accelerate disease progression!
1. What is Troriluzole?
It is a regulator of glutamate, an important neurotransmitter for communication between neurons. In particular, Purkinje cells (neurons in the cerebellum) are stimulated by this neurotransmitter. If there is an imbalance of glutamate, there can be excess activation, which can be toxic to nerve cells, which can die, causing cerebellar atrophy and producing symptoms of ataxia. Troliluzole reduces this glutamate signaling (which can be neurotoxic if excessive).
2. Which ataxias can Troriluzole help with?
Troriluzole is an experimental drug developed for the treatment of spinocerebellar ataxias (SCAs), a group of inherited neurodegenerative diseases that affect motor coordination. It is not a cure, but it is expected that Troriluzole may be beneficial for a wide range of spinocerebellar ataxias. The best response appears to be for SCA3 ataxia, but the drug appears to help other types of SCAs. In a phase 3 study, treatment with Troriluzole resulted in a 50-70% slowdown in disease progression in patients with different SCA genotypes, providing additional years of independence.
Based on these positive results, Biohaven Pharmaceuticals plans to submit a New Drug Application to the FDA for the treatment of all 50 currently known types of spinocerebellar ataxias (SCAs).
For acquired ataxias, Troriluzole may also help, as the medication acts on the regulation of glutamate to the Purkinje cells.
The same applies to Friedreich's ataxia. Although it is a mitochondrial disease, patients may benefit from the protection of Purkinje cells provided by troriluzole (in cases of excessive glutamatergic signaling).
3. How is the medicine presented?
Oral medication, one tablet is taken daily. The recommended dose is 200 mg/day (in clinical trials, the dose starts at 140 mg/day for the first month, then increases to 200 mg/day). You can take the medication with or without food.
4. What should the cost be?
IT'S STILL UNKNOWN HOW MUCH IT WILL COST IN THE US; the price in the American market will only be known after the FDA approves the drug for commercialization in the US. But considering the cost of launching drugs for rare diseases, the annual cost of Troriluzole could be high (tens of thousands of dollars per year).
5. What are the side effects?
Troriluzole is expected to be better absorbed than riluzole (the active ingredient) and cause fewer side effects. Possible side effects of Troriluzole include:
- Headache
- Nausea and vomiting
- Gastrointestinal discomfort.
- Dizziness, drowsiness, fatigue
- Rarely allergic reactions
- Change the level of some enzymes in the liver (toxicity)
Additional care - Avoid pregnancy and donating blood during treatment with Troriluzole (until there are more tests on the effects on pregnancy).
6. Which symptoms improve?
Walking and talking improved.
Reduced risk of falls.
It appeared to delay symptom progression by 50%.
Dizziness and vertigo did not improve.
Note! Biohaven is organizing a new study (EAP - expanded access program) and recruiting patients at multiple sites in the USA and Europe.
7. When will it be approved for sale in the USA?
It is expected to be approved by the FDA in 2025, but no one knows which month.
8. If approved by the FDA, when will it be available outside the USA?
It depends on the country, as each has its own regulatory process. For sale in Brazil, once approved by the FDA, Troriluzole will need to be approved by ANVISA.
Note! It is not known exactly which SCAs the FDA will approve the drug for (if at all).
Comments (Marcio Galvão)
The medication is indicated for patients with suspected glutamate regulation issues, as this is what the medication addresses. Taking Troriluzole without having glutamate excess issues can lead to improper regulation of the neurotransmitter, which can cause significant side effects.
IN MY OPINION, Troriluzole should only be prescribed by a physician after a careful evaluation, considering the potential benefits and risks for each patient (as should be the case with any medication). For those starting treatment, continuous monitoring is essential to ensure safety and efficacy.
How do you know whether a specific patient has a glutamate excess problem or not before prescribing this medication?
Determining whether a patient with ataxia has a glutamate excess problem (risk of excitotoxicity) is difficult, given that glutamate is involved in signaling throughout the central nervous system. This would require a combination of a detailed clinical evaluation with advanced laboratory and imaging tests.
- Some SCA subtypes are associated with GENETIC MUTATIONS that cause dysfunctions in glutamatergic signaling. FOR EXAMPLE, SCA1, SCA2, SCA6, SCA12.
- IN THE CASE OF SCA3, although SCA3 is not directly caused by a dysfunction in glutamate levels, there is evidence that glutamate plays a relevant role in the pathology of the disease, especially with regard to neuronal degeneration and excitotoxicity.
- Imaging test - Magnetic Resonance Spectroscopy (MRS) - Allows you to measure glutamate levels in the cerebellum (and other parts of the brain).
- PET (Positron Emission Tomography) using tracers specific for glutamate receptors, to help identify hyperactivity.
- Biomarkers: Glutamate levels in cerebrospinal fluid (CSF). Another marker would be oxidative stress (reactive forms of oxygen) can be used as indirect indicators of excess glutamate.
