Anti-Inflammatory/Neuroprotective Agents

Amyotrophic lateral sclerosis (ALS) is a progressive disease characterized by the loss of motor neurons, the nerve cells that control muscle movement. As the disease progresses, nerve cells die, leading to muscle weakness and other symptoms of the disease. A factor that contributes to disease progression is an increase in inflammation, which can accelerate the loss of nerve cells.

A number of experimental treatments are aimed at slowing the progression of ALS by reducing the inflammatory response and protecting nerve cells.


AMX0035, a treatment being developed by Amylyx, is a combination of two compounds, sodium phenylbutyrate, and tauroursodeoxycholic acid, that work together to reduce the intercellular signaling that causes inflammation and cell death. By controlling cell death, this treatment may slow nerve cell loss and the progression of ALS.


Arimoclomol is a therapy that Orphazyme and the University of Miami are developing in tandem. The treatment stimulates the release of a type of protein called “heat shock proteins,” which normally are produced in response to stress. Heat shock proteins can bind to faulty proteins, helping them to fold correctly. For misfolded proteins that have clumped or aggregated, heat shock proteins can stimulate the pathways that degrade these aggregates. Heat shock proteins also regulate programmed cell death, which is one of the ways the body gets rid of damaged cells. Through these mechanisms, arimoclomol may be able to protect nerve cells in patients with ALS.


AT-1501 is an experimental therapy being developed by Anelixis Therapeutics. The treatment contains an antibody against a protein called CD40 ligand, which is found on the surface of some immune cells. CD40 signaling is overactive in ALS. By binding to the CD40 ligand and blocking its function, AT-1501 may be able to delay inflammation and the onset of ALS symptoms.


Gilenya is a therapy being developed by the ALS Therapy Development Institute as a potential treatment for ALS. Gilenya was developed by Novartis and is approved for the treatment of multiple sclerosis (MS), another neurodegenerative disorder. It acts on a receptor called the sphingosine 1-phosphate (S1P) receptor, blocking downstream signaling. Signaling from the S1P receptor is required for immune cells to leave the lymph nodes and enter the bloodstream. Blocking the S1P receptor lowers the number of immune cells that can reach the nervous system, reducing inflammation and the symptoms of ALS.


Gleevec is an anti-cancer medication developed by Novartis. The treatment contains a small molecule that inhibits enzymes called tyrosine kinases, which are involved in signaling that is crucial for cancer cells to grow and spread. In patients whose ALS is caused by an increase in misfolded SOD1 protein within nerve cells, Gleevec may be able to reduce the levels of SOD1, but the mechanism by which this occurs is unknown.


GM6 is a potential treatment for ALS being developed by Genervon. It is a small protein molecule that may protect nerve cells and slow the progression of ALS, but the precise mechanism is unknown.

H.P. Acthar Gel

H.P. Acthar Gel is an investigational treatment for ALS being developed by Mallinckrodt Pharmaceuticals. It is administered as an injection into the skin or muscle. The treatment contains a form of the adrenocorticotropic hormone (ACTH), which acts on the adrenal glands (the small glands located over the kidneys), causing them to secrete naturally occurring steroids — cortisol, corticosterone, and aldosterone. These steroid compounds suppress the immune system, reducing inflammation throughout the body and preventing the immune system from acting on the nervous system.


Masitinib is a treatment being developed by AB Science that also acts on tyrosine kinases. Blocking tyrosine kinases has been shown to block the growth of several types of immune cells that are thought to be important in ALS disease progression. By preventing these immune cells from proliferating, the treatment may reduce inflammation in the nervous system.


MN-166 (ibudilast) is an investigational therapy being developed by MediciNova. It blocks the proliferation of a type of immune cells thought to be important in ALS disease progression, as well as reducing inflammatory signaling between immune cells.


Nurtec is a new formulation of riluzole that is placed under the tongue and dissolves in the mouth. The therapy is being developed by Biohaven Pharmaceuticals. It is a small molecule that may block the release of a neurotransmitter molecule called glutamate. In ALS, glutamate signaling is thought to increase to levels that are toxic for nerve cells. By reducing the release of glutamate, Nurtec may prevent glutamate from reaching toxic levels around nerve cells.


Telbivudine is a treatment for hepatitis B that also is being researched to treat ALS. In addition to targeting the hepatitis B DNA synthesis, telbivudine has been shown to target misfolded SOD1 protein, reducing its levels in nerve cells and potentially treating ALS.


Cell therapy using regulatory T-cells (Tregs), a type of immune cell that is involved in controlling inflammation, has been identified as a potential treatment for ALS. By infusing patients with Tregs, researchers hope to reduce the inflammatory response, thereby reducing the symptoms of the disease. A small clinical trial showed that the treatment was safe and well-tolerated. Patients also experienced a slower decline in functional abilities following treatment.


TUDCA, or tauroursodeoxycholic acid, reduces nerve cell death by acting as an antioxidant; it can bind and inactivate toxic molecules called reactive oxygen species, which damage or kill cells. TUDCA is being tested in clinical trials both alone and in combination with sodium phenylbutyrate as part of AMX0035.


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