Amyotrophic Lateral Sclerosis Epidemiology, Etiology, Pathological Mechanism, Diagnosis and Treatment

1. INTRODUCTION

Amyotrophic lateral sclerosis or commonly known as ALS is one of the major neurodegenerative diseases alongside Alzheimer’s disease and Parkinson’s disease in the United States. A-myo-trophic is derived from the Greek language. A meaning no, Myo meaning muscle, and Trophic meaning nourishment that translates to No-muscle-nourishment. With no nourishment, the tissues degenerate leading to scarring or sclerosis of the region. Lateral indicates the location in the spinal cord, responsible for effective functioning of neurons. [1] ALS is a progressive disorder that involves degeneration of the upper motor neurons (UMN) in the frontal lobe of the brain and the lower motor neurons (LMN) in the brain stem and the spinal cord.

In ALS, as motor neurons die, a person loses the ability to walk, speak, swallow, and breathe. As the degeneration advances, the muscles gradually weaken and atrophies, losing its ability to control voluntary movements. ALS may rarely impair a person’s mind or personality, but people with ALS develop cognitive problems involving memory, speech fluency, and decision-making. ALS is usually fatal within 2-5 years of diagnosis. [2]

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2. BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Jean-Martin Charcot first described the disease in 1869. He used ALS as a prototypic example of his research techniques to coin the term “méthode anatomoclinique.” This method provided a disciplined and systematic approach to classify neurological diseases based on integrating clinical signs and anatomical lesions. [3] Because of Charcot’s fundamental contributions, the term “Charcot’s disease” is used as a synonym for amyotrophic lateral sclerosis.

ALS is also referred to as ‘Lou Gehrig’s Disease’ as it caused the death of the New York Yankees baseball player, Lou Gehrig in 1939. ALS can affect any human being regardless of their age, sex, or ethnic groups. For example, the famous astrophysicist Stephen Hawking was diagnosed with ALS at a young age and has survived for over 50 years. Mao Zedong, founder of the People’s Republic of China, Lane Smith- an American actor, O.J. Brigance- a professional football player, have been victims of ALS. [1]

In the summer of 2014, social media was taken by storm with videos of people pouring ice water on themselves for the Ice Bucket Challenge. This initiative was introduced by Pete’s Frates, a professional baseball player, who helped in increasing awareness for ALS and raised millions of dollars for research. The Ice Bucket Challenge was an enormously successful Internet phenomenon accepted by many actors, philanthropist, artists, and athletes. [4] Over 17 million people uploaded their challenge videos to various social media sites, and these videos were watched by 440 million people! The ALS Association collected $115 million in a six-week span from the ALS Ice Bucket Challenge. The ALSA reports that a majority of this fund was allocated for research and the rest was used for patient and community services, education, and fundraising. [4], [5]

3. EPIDEMIOLOGY

ALS is the most frequent adult-onset motor neuron disease. It is characterized by both upper and lower motor neuron degeneration and has a median survival of 2–5 years. [2] The worldwide annual incidence of ALS is about 1.9 per 100,000 individuals. Since, almost all patients with ALS die of their disease, mortality rates for ALS individuals remains constant. As per the recent analysis, the number of ALS cases worldwide is predicted to rise by 69% over the next 25 years. According to the United Nations, the number of individuals above age 60 is expected to increase rapidly. This increase is particularly due to improving healthcare and economic conditions among developing nations. [6]

1. Age

ALS can strike at any age, although symptoms develop as one grows older. Mean age at onset is 58 to 63 years for sporadic ALS and 40 to 60 years for familial ALS. [2] As per the Centre for Disease Control and Prevention results, individuals with those aged 18 to 39 years had the least prevalence rate (0.5 per 100,000 persons), and the age group 70 to 79 years had the highest prevalence rate (17.0 per 100,000 persons). [7], [8] The prevalence of ALS increases with age.

2. Gender

It is observed that men are at a higher risk to develop ALS than women, leading to a male-to-female ratio of 1.2–1.5. [7] Although as age increases, the incidence of ALS between men and women disappears. Few studies suggest that military veterans are twice more prone to ALS, especially those deployed during the Gulf War. [2] Possible risk factors for veterans include exposure to lead, pesticides, and diverse environmental toxins.

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3. Race and ethnicity

ALS can affect any person with no racial, ethnic, or socioeconomic boundaries. The prevalence rate for Caucasians was 2-fold greater than in African-Americans. Caucasians have a prevalence rate of 4.2 per 100,000 as compared to 2.0 per 100,000 for African-Americans. [7] Some geographic regions have an unusually high incidence of ALS, specifically Guam and the Kii Peninsula in Japan. The incidence of ALS in these regions is high due to environmental factors, especially a neurotoxic non-protein amino acid, β–methylamino-L-alanine (BMAA) produced in the seeds of Cycas micronesica. [2] It is hypothesized that patients in these regions may have a genetic susceptibility because of their inability to prevent BMAA accumulation.

4. CLINICAL FEATURES & SYMPTOMS

Amyotrophic lateral sclerosis is a condition involving both UMN and LMN. The progression and spread of the disease can be both local and between neuro-anatomically linked regions. The identification of specific phenotypes helps in prognosis and survival, and also for their enrolment in clinical trials. The clinical manifestation of ALS helps in learning about the progression of the disease in an affected individual. The important presentations of ALS are described below;

1. Limb onset ALS

Limb-onset ALS is the dominant feature with 70% of the cases among patients. [9] The main clinical feature in Limb-onset ALS is a combination of UMN and LMN damage involving brainstem and spinal cord regions. Patients with lower limb onset may complain of tripping, stumbling while walking or running. Patients with upper limb onset face difficulty in performing actions such as eating, writing, or picking up small objects.

2. Bulbar onset ALS

Patients with bulbar onset present both upper and lower motor neuron signs. Dysarthria is a characteristic feature in patients with bulbar-onset ALS. Bulbar upper motor neuron symptoms include speech problems such as slurring, hoarseness, drooling, and distorted speech are typical symptoms. [10] Bulbar lower motor neuron signs include tongue wasting, fasciculations, and flaccid dysarthria. Some ALS patients show pseudo-bulbar symptoms like exaggerated involuntary emotional responses. Episodes of intense laughter may be followed at once by tears.

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3. Primary lateral sclerosis

Primary lateral sclerosis is a variant of ALS with UMN involvement. It is a slow progressive type but affects the whole body. It is a rare motor neuron disease and spreads from the bulbar region to limbs. [9], [10] Primary lateral sclerosis is characterized by spasticity, weakness, pathologically hyperreflexia, and pseudo-bulbar speech.

4. Progressive muscular atrophy

Progressive muscular atrophy is another variant of ALS, represented by progressive LMN signs without clinical evidence of UMN dysfunction. [9] Symptoms of this disease are fasciculation, atrophy, and muscle weakness.

5. ETIOLOGY

Although the etiology of ALS is not entirely understood, it can be classified into Familial ALS and Sporadic ALS. This section explains in brief the genetic and non-genetic causative agents for ALS.

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5.1 Familial ALS (FALS)

Familial ALS means that there is more than one occurrence of the disease in a family. FALS represents about 5 ~ 10% of all ALS cases diagnosed. [11] FALS can be further categorized by mode of inheritance and sub-categorized by the specific gene. Over 25 causative genes have been linked to hereditary ALS. FALS can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner depending on the gene involved.

5.1.1 Autosomal Dominant (AD)

Autosomal dominance is a characteristic pattern of inheritance wherein a single copy of the disease-associated gene is sufficient to cause the disease. A few examples of AD genes are Superoxide dismutase1 (SOD1), Fused in sarcoma (FUS), TAR DNA-binding protein (TARDBP), and Chromosome 9 open reading frame 72 (C9orF72).

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• ALS1: Superoxide dismutase 1 (SOD1): SOD1 gene can be described as an autosomal dominant and autosomal recessive in the FALS pedigree. Mutations in SOD1 gene accounts for 20% of familial ALS and 5% of sporadic disease. [12] SOD1 converts harmful superoxide radicals to molecular oxygen and hydrogen peroxide thus protecting cells from the accumulation of free radicals. [13] Mutations in SOD1 impair the effective functioning of this protein.

• ALS6: Fused in Sarcoma (FUS):  FUS is a nucleoprotein that is responsible for DNA repair, regulation of transcription, and RNA splicing. Over 60 FUS mutations have been identified in 3-5% of patients with familial ALS and in 1% of patients with sporadic ALS. [12] ALS-linked mutations in the FUS gene disrupt the effective functioning of DNA and RNA metabolism in the cell. The phenotypes associated with FUS mutations include adult-onset ALS, Juvenile-ALS, ALS-Frontotemporal dementia, and rarely pure Frontotemporal Dementia (FTD).

• ALS10: TAR DNA Binding Protein (TARDBP): The TARDBP gene encodes a DNA and RNA-binding protein called TDP-43. In healthy neurons, TDP-43 is located in the nucleus and regulates gene expression, RNA transcription, and splicing. Pathogenic mutations cause the TDP-43 protein to attain a hyper-phosphorylated and ubiquitinated form of RNA and DNA binding protein that is accumulated in neurons and spreads along the brain and spinal cord of ALS patients. Impaired TDP-43 functioning leads to neuronal degeneration with a limb or bulbar onset ALS. [11], [13] Other phenotypes associated with TARDBP mutations include Frontotemporal dementia (FTD), and ALS-FTD. ALS and FTD are heterogeneous in nature and share some clinical, neuropathological, and genetic features. Around 5–10% of ALS patients develop FTD. [14] Common features of ALS and FTD include cognitive deficits in attention, problem-solving, preservation of perception, and spatial functions.

5.1.2 Autosomal Recessive (AR)

In an autosomal recessive inheritance, the disease-associated gene must be inherited from both parents in order for an individual to develop the condition. ALSIN and OPTN (Optineurin) genes are common examples of AR inheritance in ALS.

• ALS2: ALSIN: ALS2 activates multiple proteins called GTPases that are essential for maintenance of motor neurons. [12] Mutations in ALS2 are responsible for autosomal recessive and early-onset forms of UMN diseases such as Juvenile amyotrophic lateral sclerosis (JALS). JALS is frequently caused by mutations in ALS2 genes and seldom caused by mutations in SETX (Senataxin), UBQLN2 (Ubiquilin2), and FUS genes. [15] JALS is a rare, severe motor neuron disease with a mean onset age of 6.5 years. It is characterized by limb and facial spasticity, gait, dysarthria, sensory disturbance, and bladder dysfunction.

• ALS12: Optineurin (OPTN): Mutations in OPTN have been reported in both SALS and FALS cases in either an autosomal dominant or recessive manner. OPTN gene regulates receptor-interacting kinase-1 enzyme (RIPK1), which plays a key role in inflammation and cell death. [16] Mutations in the OPTN gene causes neurotoxicity through dysmyelination and axonal degeneration.

5.1.3 X-Linked

In X-linked dominant inheritance, the gene responsible for the condition is located on the X chromosome. Mutation in either male and female copy of the gene can cause the disorder. Pathogenic variants in gene UBQLN2 (Ubiquilin 2) is related to X-linked dominant ALS.

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• ALS 15/ Ubiquilin 2 (UBQLN2): Pathogenic variants in UBQLN2 encodes the ubiquitin-like protein ubiquitin-2, causing X-linked dominant ALS and ALS/dementia. Mutations in the UBQLN2 gene causes inclusions that can be seen in the spinal cord of affected patients. These inclusions are also seen for other ALS proteins such as TDP-43, FUS, and OPTN. ALS 15 can be an adult or juvenile onset disease. [12], [13]

5.2 Sporadic ALS (SALS)

Sporadic ALS is the most prevalent form of ALS consisting up to 90 to 95 percent of all ALS cases. [11] This type of ALS occurs sporadically with no known family history. Although the etiology of sporadic ALS is unknown, epidemiological data indicate that environmental & genetic factors contribute to its pathogenesis. Some of the risk factors that have increased ALS incidence are listed:

• Smoking: Cigarette smoking is the most consistent non-genetic risk factor for ALS. Cigarette smoke increases the probability of developing ALS through increased oxidative stress, inflammation, and neurotoxicity by heavy metals in cigarettes. Exhaled cigarette smoke has formaldehyde that is associated with higher mortality rates in ALS patients. [2]
• Physical Fitness: An increased risk of ALS is seen among athletes and individuals who engage in strenuous physical activities. Strenuous physical activity, repeated head injuries, use of illicit drugs, act as potential risk factors for ALS. Repeated head injuries cause chronic traumatic encephalopathy which has been proposed as a reason for ALS among professional athletes and military veterans. [2]
• Heavy Metals: Increased levels of lead in blood and bone were found to be associated with ALS.  Lead and Manganese have neurotoxic properties that get accumulated in the nervous system causing damage to the neurons. [2] Other metals such as copper, aluminum, arsenic, uranium, cadmium, zinc, cobalt, and vanadium are found in significantly higher concentrations in the CSF of ALS patients when compared to healthy individuals.
• Radiation & Electromagnetic field: Magnetic fields, electrical fields, contact currents, micro-shocks, are often associated with occupational occupation exposing to involving low-frequency Electromagnetic field (EMF). Low-frequency electromagnetic waves produce oxidative stress that can disable the antioxidant properties of cells, leading to ALS. [17] However, none of the current studies report a conclusive connection between EMF exposure and oxidative stress in ALS development.

Several other factors such as pesticides, viruses, occupational workers (electrical workers, construction workers), dietary habits are proposed to be associated with ALS.

The etiology of sporadic ALS is complex. A combination of oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, inflammation, and apoptosis has been suggested as possible causes. Single-nucleotide polymorphisms (SNPs) in the paraoxonase gene cluster (PON) have been associated with sporadic ALS. PON enzymes are seen in insecticides, nerve gas agents, and in statin drugs. [18] Another example would be C9orF72 (Chromosome 9 open reading frame 72) which is a frequent cause of ALS, is responsible for about 10% of sporadic cases. [19] C9orf72 gene is also associated with familial ALS, Frontotemporal Dementia (FTD), and ALS with FTD. Few other examples of FALS genes mutations and variants occurring in sporadic ALS are ATXN2 gene, SETX gene, FUS gene. [19] These reports reinforce the concept that familial and sporadic ALS are not mutually exclusive categories but connected to each other.

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6. PATHOLOGICAL MECHANISM

Learning in depth about the molecular mechanisms for the degeneration of motor neurons in ALS can help in better understanding of the disease and can provide insight into developing newer strategies and treatments. This section provides a brief overview of the molecular and cellular mechanisms that have been proposed to contribute to ALS pathogenesis.

6.1 Glutamate Excitotoxicity

Glutamate is an important excitatory neurotransmitter in the central nervous system. During a normal neurotransmission process, glutamate is released into the synaptic cleft, where it activates postsynaptic receptors. This activity is regulated by transporter proteins, called excitatory amino acid transporters (EAATs). [20] Excessive activation of glutamate receptors and failure in clearing the neurotransmitter from the synaptic cleft can induce injury to neurons. This abnormal receptor activity leads to a massive influx of calcium that triggers apoptotic pathways causing motor neuron death and degeneration.

6.2 Mitochondrial Dysfunction

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Mitochondria are the most important organelles for cellular respiration, energy production, calcium homeostasis, and apoptosis. They represent a primary site for intracellular production of reactive oxygen species (ROS), a major source of oxidative stress, that impairs the normal functioning of mitochondria. Hence, any structural alterations or mutations in mitochondria can lead to the pathogenesis of ALS. [21]

6.3 Oxidative Stress

Free radicals or ROS are natural byproducts of oxygen metabolism. Oxidative stress is caused when the production of ROS is greater than the capacity of cells to remove them. This excessive accumulation of ROS causes permanent damage to cell structures, DNA, and RNA causing motor neuron degeneration. SOD1 is an important protein to prevent oxidative damage in cells. [21] Mutation in the SOD1 gene causes disruption of cellular functions and cytotoxicity. This can be confirmed by testing the levels of oxidative stress. 3-nitrotyrosine (3-NT) is an established biomarker for oxidative stress and the levels of 3-NT is elevated in serum, urine, and CSF samples of ALS patients. [22]

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6.4 Neuroinflammation

A familiar characteristic of ALS and other neurodegenerative diseases is the neuroinflammation. In the CNS, microglial cells are macrophages that act as the first line of defense against infections or injuries, thereby protecting motor neurons and astrocytes. Microglial cells have immunological properties, that can be either beneficial or harmful to motor neuron survival. As ALS progresses and the motor neuron damage worsens, the astrocytes and motor neurons release mutated SOD1 proteins that stimulate the activation of microglial cells. Activated microglial cells cause switch from neuroprotective and anti-inflammatory to a neurotoxic and pro-inflammatory phenotype. [21], [22]

7. DIAGNOSIS

The early and accurate diagnosis of ALS can be challenging because of the complex and heterogeneous nature of ALS. There are no definitive diagnostic tests to prove ALS, hence differential diagnosis and investigations are conducted for an individual patient. This includes obtaining a thorough patient history, conducting neuroimaging scans, electromyography, laboratory tests, and genetic testing.

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1. Diagnosis Criteria

In the late 1990s, diagnostic criteria were developed to standardize diagnosis of ALS and research studies for clinical trials.

• The El Escorial criteria: As per this criterion, five categories of certainty of ALS were defined: clinically definite, clinically probable, clinically probable with laboratory support, clinically possible, and clinically suspected ALS. [23] The El Escorial criteria required clinical evidence in three of the four anatomic regions to be confirmed as definite ALS. These restrictions made it difficult to diagnose individuals with ALS. To improve the speed and certainty of diagnosis, laboratory tests were introduced as diagnostic tools to exclude differential diagnosis. This revised criterion was added to the El Escorial criteria and was renamed to the Airlie House Criteria in 1998. In 2008, neurophysiological measurements for LMN and UMN degeneration was incorporated, and it was known as Awaji-shima criteria. The Awaji criteria classifies the certainty level of ALS into three categories: Clinically definite ALS, Clinically probable ALS, and Clinically possible ALS. [23]

• The Japanese ALS severity classification: This categorization varies from El Escorial diagnostic criteria based on the functional severity of the patients. The Japanese ALS severity can be classified as;

Grade 1: Able to work or perform housework;

Grade 2: Independent living but unable to work;

Grade 3: Requiring assistance for eating, excretion, or ambulation;

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Grade 4: Presence of respiratory insufficiency, difficulty in coughing out sputum, or dysphagia;

Grade 5: Using a tracheostomy tube, tube feeding, or tracheostomy positive-pressure ventilation.

2. Differential Diagnosis

The primary diagnosis of ALS is conducted by clinical examination and series of diagnostic tests that help to exclude diseases that mimic ALS. Some of the conditions that mimic ALS are Cervical spondylotic myelopathy, Kennedy disease (KD), Multiple Sclerosis, Parkinson’s diseases, and Post-polio syndrome (PPS). The following table shows a list of differential diagnosis and clinical overlap with ALS; [24]

For example, Kennedy disease (KD), known as spinobulbar muscular atrophy, is an X-linked disorder of brainstem and spinal cord. KD symptoms demonstrate slow progressive LMN signs in the bulbar region and proximal limbs, fasciculations, mild cognitive impairment, sensory disturbance, and gynecomastia. [24] In addition, increased creatine kinase (CK) levels and low amplitude of sensory nerve action can help to differentiate KD from ALS. Progression of KD is slower than that of typical ALS. To confirm this diagnosis, a genetic test for detection for KD is also required.

3. Diagnostic Tests

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Although the essential diagnostic criteria of ALS are defined by the El Escorial criteria, many misdiagnoses still occur. ALS mimic syndromes can be in terms of the anatomy, symptoms, or clinical manifestations. There is no single confirmatory test for ALS, but an extensive workup can help to rule out differential diagnosis. A comprehensive diagnostic workup includes most of the following procedures: [23]

• Electro-diagnostic test: Nerve Conduction studies and Needle Electromyography can detect the presence of fibrillation/fasciculations and sharp positive waves (together referred to as spontaneous activity). These tests can help in definitive diagnosis of ALS.

• Radiology tests: MRI for C-spine, lumbar spine, and thoracic spine.

• Laboratory test: CSF analysis, 24-hour urine collection for heavy metals, muscle biopsy, blood work including CBC, B12, folate, Creatine Kinase (CK), Serum protein electrophoresis (SPEP), Urine protein electrophoresis (UPEP). (CK, SPEP, and UPEP show elevated levels in ALS patients as compared to healthy individuals).
• Neurological test: Physical & mental health examination, cranial & motor nerves examination, sensory examination, gait, reflexes, etc.

• Genetic testing

A definitive diagnosis of ALS requires evidence of LMN and UMN degeneration, signs of progression, and spread of neurological symptoms within the anatomical region. The electrophysiological, laboratory, and neuroimaging results should not show evidence of any other pathological symptoms that mimic ALS.

4. Functional Endpoints

Muscle strength and function are considered the most important endpoints that show effectiveness and consistency for any symptomatic treatment. For ALS, they can be assessed by;

• ALS Functional Rating Scale (ALSFRS):The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and the revised version that includes respiratory function (ALSFRS-R) is the most extensively used instrument to measure the efficacy of a drug in ALS clinical trials. The ALSFRS-R is an evaluation technique for monitoring the progression of disability in ALS patients based on twelve questions for fine motor, gross motor, bulbar, and respiratory functions. [25] Each question has five possible responses and each item is scored from 0 to 4 point range. Higher scores suggest greater functional ability.
• Percent Forced vital capacity (%FVC): %FVC is method for the assessment of Respiratory Function in ALS patients. A decrease in %FVC (not greater than 50%) is considered as a criterion for respiratory support. [25]

Other scales that measure functional disability are the Norris scale, the Appel Scale, and the Pinch grip strength method. However, the ALSFRS-R is the preferred scale. If it is not used as primary endpoint, it can be used as a secondary one.

8. TREATMENT

Although pathological mechanisms have been explained, ALS remains incurable disease because of failure of clinical trials and lack of any effective therapy. The rapid advancement in genetic discoveries in ALS emphasizes the point that ALS is a multi-subtype syndrome rather than a single disease. This can be one of the reasons why many previous clinical trials have failed. This section will review the recent developments in therapeutic compounds and alternative therapies for ALS.

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1. Therapeutic Approaches in ALS

As the pathogenesis of ALS is complex, there is no effective treatment to cure ALS. Nevertheless, there are several therapeutic strategies can slow the progression of symptoms, prevent complications, and prolong survival.

1.      Radicava

The FDA approved Radicava in May 2017 in the United States, based on a six-month clinical trial conducted in Japan and granted it an Orphan drug designation. Radicava was discovered and developed by Mitsubishi Tanabe Pharma Corporation and will be commercialized in the United States by MT Pharma America. [26] It has been approved as a treatment option for ALS in Japan and South Korea. The drug is primarily known to slow the decline in physical function and delay the progression of ALS.

1. Physical Properties

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Edaravone is an active ingredient in Radicava, which is a member of the substituted 2-pyrazolin-5-one class. The chemical name of edaravone is 3-methyl-1-phenyl-2-pyrazolin-5-one. The molecular formula is C₁₀H₁₀N₂₀ and the molecular weight is 174.20. Edaravone is a white crystalline powder and has a melting point of 129.7°C. It is soluble in acetic acid, ethanol, methanol, and slightly soluble in water. [27] Radicava injection supplied for intravenous infusion contains 30 mg edaravone in 100 mL isotonic, sterile, aqueous solution.

2. Mechanism of Action

Radicava (Edaravone/MCI-186) is a neuroprotective drug that has properties of a free radical scavenger. Since oxidative stress is one of the major cause ALS, removal of free radicals may offer therapeutic benefits. Several free radical scavengers have been assessed for their efficacy, but only a few drugs have shown success in studies conducted. Edaravone is known to eliminate lipid peroxides and hydroxyl radicals and protects neurons from increased oxidative stress. [28] A reduced concentration of an oxidative stress biomarker, 3-nitrotyrosine, is seen in the cerebrospinal fluid. Edaravone can readily cross the blood-brain barrier (BBB), thereby explaining its efficacy while other scavengers have failed to demonstrate such effectiveness. [29] Thus, treatment with Edaravone slows the progression of functional motor disturbances in ALS patients

3. Pharmacokinetics (PK) of Edaravone [30]

• Absorption– Edaravone is administered by IV infusion. The maximum plasma concentration of edaravone is reached by the end of infusion. Edaravone does not accumulate in plasma even after administration of multiple doses.

• Distribution– Edaravone is bound to human serum protein, albumin (92%), with no concentration dependence in the range of 0.1 to 50 micromol/L.

• Metabolism– Edaravone is metabolized into sulfate and glucuronide conjugates in the liver. These metabolites are not pharmacologically active and do not inhibit or induce isozymes. The mean terminal half-life of edaravone is about 4.5 to 6 hours. The half-life of its metabolites is 2 to 2.8 hours.
• Excretion– Approximately 70-90% of Edaravone is excreted in the urine as its glucuronide conjugate form and about 5-10% of the dose is recovered in the urine as sulfate conjugate form. Only about 1% or less form of the dose is detected in the urine as in an unchanged form.

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4. Toxicology Assessment [30, 31]

The toxicity potential of edaravone has not been assessed adequately. There is no reported evidence of carcinogenic abnormalities. Edaravone was also tested negative for bacterial reverse mutation in Chinese hamster lung chromosomal aberration (in vitro) and mouse micronucleus assays (in vivo). Intravenous administration of edaravone had no effect on fertility. However, disruption of the estrus cycle and irregular mating behavior was noted at the highest dose tested.

5. Adverse Reactions [30, 31]

Some common adverse reactions that occurred in Edaravone treated patients were contusion, gait disturbance, and headaches. Adverse effects of edaravone were observed in embryo development studies that include decrease in fetal body weight, delays in markers of development, and increased mortality. There were a few deaths in edaravone controlled studies as well as in placebo-treated patients. These deaths were related to respiratory failure which is the most common cause of death in ALS.

6. Specific Population Studies [30, 31]

Population PK analysis indicates that the pharmacokinetics of edaravone is not affected by gender, age, race, or weight. There is a fetal developmental risk associated with the use of edaravone in pregnant women. However, there is no adequate data to prove the presence of edaravone in human milk, effects of the drug on milk production, or on the breastfed infant. No safety concerns related to hepatic or renal impairment has been reported.

7. Clinical Trials

The edaravone clinical development program for edaravone started in 2001for treatment of ALS in Japan. The ALS clinical trial program was conducted to explore efficacy and safety of edaravone and consisted of one Phase II and four Phase III studies. All the clinical trials were conducted in accordance with Good Clinical Practice and the guiding principles of the Declaration of Helsinki.

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• Study 12 (MCI 186-12) [31]: Study 12 was a Phase II, open‐label, exploratory study in ALS patients. In this study, 5 patients were administered 6 cycles of edaravone 30 mg/day, and 14 patients were administered 6 cycles of edaravone 60 mg/day. The first cycle consisted of 2 weeks of daily infusion of the drug followed by 2 weeks without treatment. Based on results, efficacy was assessed for the 60 mg/day group and was selected as the dose to be tested in all Phase 3 studies. The primary endpoint was the change in the revised ALS functional rating scale (ALSFRS-R) that showed improved scores for patients on edaravone treatment.

• Study 16 (MCI 186-16) [31], [32]: Based on phase II preliminary results, phase III studies (MCI 186-16) were conducted to evaluate the efficacy and safety of edaravone at a dose of 60 mg per day. This was a multi-center, placebo-controlled, double-blind, parallel-group comparative study in ALS patients. This study enrolled 206 ALS patients of Grade 1 and 2 (Japanese ALS severity grade) and patients with definite ALS, probable ALS, or probable laboratory supported (ALS El Escorial Revised Airlie House criteria) within 3 years of screening. Patients were randomized to receive either edaravone or placebo for 24 weeks. The primary efficacy endpoint was the change in the ALSFRS‐R score from baseline to the end of 24 weeks. It was concluded that edaravone is effective in patients with mild ALS (Japanese ALS severity grade 1 & 2).

• Study 17 (MCI 186-17) [31], [33]: This study was a placebo-controlled extension of study 16, in which patients who received edaravone in Study 16 were re-randomized to receive edaravone or placebo, while patients who received placebo in study 16 were switched to edaravone. The primary efficacy endpoint was the change in ALSFRS‐R score. That study did not provide any useful efficacy information.

• Study 18 (MCI 186-18) [31], [34]: Thisphase III study was an exploratory, randomized, placebo-controlled study in patients with advanced ALS (Japanese ALS severity grade 3). The primary efficacy endpoint was the change in ALSFRS‐R score. This study yielded no significant difference in the scores between the treatment group and the placebo group. Study 18 demonstrated that edaravone lacks efficacy in patients with advanced ALS severity.

• Study19 (MCI 186-19) [31], [35]: Study 19 (MCI 186-19) was a second confirmatory Phase III study comprising two study periods; a randomized, placebo-controlled period of six cycles for 137 subjects and an active extension period of six cycles for a subset of ALS patients. This study design was similar to study 16 and used the same primary endpoint, i.e. change in ALSFRS‐R score at the end of 24 weeks. Secondary endpoints such as disease progression, percent FVC, Modified Norris Scale score, and Pinch grip strength were examined. The primary population used for the efficacy analysis was the Full analysis set (FAS) and Analysis of covariance was used for ALSFRS-R. The primary endpoint analysis showed a significant difference, favoring edaravone over the placebo group (ALSFRS‐R score change of ‐7.50 for placebo and ‐5.01 for edaravone, p=0.0013). Statistically, the rate of decline in physical function was by 33 percent or 2.49 ALSFRS-R points. [36] All the secondary endpoints demonstrated a nominally significant score that favored Edaravone. The level of CSF 3-Nitrotyrosine (a biomarker for oxidative stress) was lower in most of the patients on edaravone treatment group, suggesting that edaravone could protect neuronal cells from oxidative stress and delay progression.

The following table provides a snapshot of the important clinical trial information for Edaravone.

Table 1: Studies in the ALS Development Program