Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a rare and devastating neurodegeneration of the upper motor neurons in the motor cortex and the lower motor neurons in the brainstem and spinal cord. Patients experience progressive weakness of upper and lower limb muscles as well respiratory and bulbar muscles. Although the clinical course is variable, mortality due to respiratory failure is common within 2 to 3 years of onset of symptoms. The global incidence of ALS is estimated at 2 per 100,000 persons and appears to be increasing in recent years.   The prevalence is estimated at approximately 6 to 9 per 100,000 persons. Currently, approved treatments for ALS include Rilutek®, Radicava®, Relyviro®, and QALSODY®. These drugs have modest effects on disease modification and on survival. Hence, there is a large unmet need among patients with ALS.

ALS and Inflammasome Activation

Several misfolded proteins implicated in the pathogenesis of ALS, including TDP-43, SOD1G93A, Pr50, and poly GA aggregates induce inflammasome activation.  The expression of multiple inflammasome components, including NLRP3, NLRC4, IL-18, IFN-γ and Caspase-1, is increased in post-mortem tissue and circulation of patients with ALS, as well as, in many animal models of the disease. Collectively, these data support the concept that inflammasome inhibition could be beneficial in patients with ALS.

K9 and inflammasomes

Kamuvudine-9 (K9) inhibits inflammasome activation in multiple animal models and inhibits IL-1β, IL-17, IL-18, and IFN-γ, as well as the Th1 and Th17 lymphocyte axes in animal models.  K9 also reduced serum neurofilament light chain (NfL) levels by 98% in an animal model of neurodegeneration. This has particular relevance to ALS since QALSODY recently received accelerated approval from the FDA for ALS on the basis of its ability to reduce plasma NfL levels by approximately 50%.