Neurodegenerative Diseases – Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is one of the motor neuron diseases, classified as a neurodegenerative disorder, leading to muscle atrophy and weakness throughout the body, ultimately causing physical disabilities.

In 2014, the ALS Ice Bucket Challenge was launched by the ALS Association in the United States, gaining global attention and raising funds for amyotrophic lateral sclerosis.

The onset of ALS is typically between 40 to 70 years old, with an average age of 55, and the prevalence is 20% higher in males than females. As age increases, the incidence of ALS becomes more similar between males and females. In the United States, there are approximately 5,000 to 6,000 new diagnoses each year, while in Taiwan, there are around 300 to 500 new cases annually.

Around 90% of ALS cases have no clear family history or genetic mutation as a cause. The remaining 5-10% of cases are known as familial ALS (FALS), which are inherited from known mutated genes related to ALS.

Common neurodegenerative diseases, including ALS, Parkinson’s disease (PD), Alzheimer’s disease (AD), Spinocerebellar Atrophy (SCA), Multiple sclerosis (MS), Huntington’s Disease (HD), and Wilson’s Disease, primarily involve the gradual degeneration of neurons in the brain and spinal cord. As brain and spinal cord neurons are generally non-regenerative, excessive damage is irreversible, leading to ongoing deterioration over time and ultimately resulting in functional impairments.

Background of ALS

Lack of Effective Treatment: Currently, there is no cure for ALS, and available treatments can only slow disease progression and improve the quality of life.
High Fatality Rate: According to statistics from the ALS Association, patients typically have an average survival of about 2 to 5 years after onset, although this can vary among individuals, with only 10% of patients surviving beyond 10 years. ALS patients usually experience progressive neuro-muscular atrophy, limb paralysis, speech and swallowing difficulties, and eventually respiratory failure within 2-3 years, leading to long-term reliance on ventilators, ultimately resulting in death as the symptoms continue to worsen.
Numerous Celebrities Afflicted: Renowned physicist Stephen Hawking in the UK, New York Senator Jacob Javits, former US Vice President Henry A. Wallace, and Taiwanese entertainment figure Ma Chi-Chin are among the many celebrities who have lost their lives to this disease.
Diagnosis: Early symptoms of ALS are challenging to detect, with typical manifestations being significant weakness or atrophy in the limb muscles, such as difficulty using hands adroitly or evident dragging or stumbling while walking. Additionally, 25% of patients may experience abnormalities in speech or swallowing. Subsequently, they begin to lose the ability to perform daily activities, such as walking, dressing, or holding utensils, and may develop obvious joint stiffness and muscle pain. Speech becomes increasingly unclear, swallowing becomes difficult, and rapid weight loss occurs. As leg weakness progresses, patients may initially use canes or walkers for support but ultimately become wheelchair-bound or bedridden. The progression of the disease can be measured clinically using the Revised ALS Functional Rating Scale (ALSFRS-R), which includes 12 items for clinical interviews or self-examination questionnaires, scored from 0 to 48 (with 48 being normal function).
In the late stages of ALS, patients may appear as motionless as a vegetative state, but they might still retain consciousness and awareness, unable to communicate effectively with the outside world. For patients, this is a torment more distressing than death itself.

Current Treatment Options for ALS

Chemotherapy

The US FDA has approved four drugs for the treatment of ALS. One of them is Riluzole, which can slow disease progression and increase the patient’s survival time. Another is Edaravone, which is used for specific types of ALS and helps reduce oxidative stress damage to motor neurons. The third is Relyvrio, approved in 2022, containing a combination of two drugs with antioxidant and anti-inflammatory effects, protecting nerve cells from oxidative stress and inflammation damage. The fourth is Qalsody, a newly approved drug in 2023, and the first antisense oligonucleotide (ASO) therapy targeting the genetic cause of ALS.

Unfortunately, none of these treatments can fully cure ALS.

Supportive Therapy

The medical team provides symptom management and support based on the course of the disease, including pain control, muscle spasm management, slowing muscle atrophy, and therapies for swallowing and speech difficulties, as well as respiratory support, etc.

Current ALS Treatment Reference Drugs

Currently, available drugs can only slow down the disease progression, with limited improvement in patients’ survival and quality of life. Therefore, there is an urgent need for more effective drugs to benefit patients.

QALSODY™ (Tofersen)

Qalsody is a newly approved ALS drug by the US FDA in April 2023. It requires administration through intrathecal injection performed by healthcare professionals experienced in lumbar puncture.
It is a nucleic acid therapy that interferes with the expression of the SOD1 gene, blocking the synthesis of abnormal SOD1 protein. Abnormal SOD1 protein is considered a key factor in disease progression in some ALS patients. Tofersen aims to reduce the accumulation of abnormal SOD1 protein, thereby slowing down the progression of ALS.
Clinical trial results showed a significant reduction in plasma NfL concentration in patients with SOD-1 gene mutations receiving Qalsody treatment at week 28. This suggests that patients may achieve clinical benefits.
The most common side effects include pain, fatigue, joint pain, increased white blood cell count in cerebrospinal fluid, and muscle pain.

RELYVRIO™ (AMX0035, sodium phenylbutyrate and taurursodiol)

New Drug Approved by the US FDA in September 2022. Developed by Amylyx, this new drug is a combination of two medications, sodium phenylbutyrate (PB), and tauroursodeoxycholic acid (TURSO). PB is known for its antioxidant and anti-inflammatory properties, believed to protect nerve cells from oxidative stress and inflammation. TURSO, on the other hand, is thought to inhibit cellular stress and reduce cell apoptosis, contributing to the maintenance of healthy nerve cells.
Clinical trial results showed that in the RELYVRIO treatment group, the average baseline total score of the ALS Functional Rating Scale-Revised (ALSFRS-R) at week 24 was 29.06, which declined less compared to the placebo group with 26.73.
The most common side effects include diarrhea, abdominal pain, nausea, and upper respiratory tract infections.

Rilutek（Riluzole）

This drug is related to the inhibition of excitatory neurotransmission associated with glutamate antagonism. Glutamate itself is an excitatory amino acid believed to be associated with excitotoxicity leading to neurodegeneration. However, the exact cause of ALS remains unknown, and this is one of the possible hypotheses.
The drug has been reported in the brochure to extend survival time or delay the use of mechanical ventilation in end-stage ALS patients. Clinical trial results showed that the median survival period in the treatment group was 17.7 months, which was higher than the placebo group with 14.9 months.
Some potential side effects may include weakness, fatigue, nausea, and abnormal liver function tests.

Radicava® (Edaravone)

Intravenous injection formulation, the active ingredient of which is Radicut, exerts its effect as a free radical scavenger, preventing oxidative stress-induced damage to neurons and slowing down the decline of functional loss in ALS patients. This antioxidant approach is believed to provide neuroprotective effects to the nervous system, thus slowing disease progression or additional damage to neurons.
Compared to the placebo group, patients treated with Edaravone showed a significantly smaller decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores (-5.01) compared to the placebo group (-7.50).
Common side effects include nausea, vomiting, headache, and fatigue.

Investigational Drugs

HK-001 Soft Capsules >>more

The HK-001 soft capsules developed by Everfront Biotech Inc. contains a small molecule active pharmaceutical ingredient EF-API-001 produced under PIC/S GMP standards. Through targeted inhibition of mTor and suppression of excessive autophagy, it aims to delay the progression of ALS in patients.
The HK-001 capsule is an oral dosage form, and two improvements were observed in animal testing results (ALS mice, SOD1^G93Amice):
- Delayed onset of ALS progression: Using a BBB scale (Basso, Beattie and Bresnahan scale) score of less than 15 as the disease onset threshold, it was observed that the onset time of ALS in mice orally administered with HK-001 was delayed compared to the control drug Riluzole.
- Prolonged survival in ALS: The survival of ALS mice orally administered with HK-001 was superior to the untreated group and also superior to the control drug Riluzole.

Care and Considerations for ALS Patients

Assistance with Activities of Daily Living

Due to muscle weakness, ALS patients may have difficulty completing daily activities such as eating, bathing, and dressing. Family members can provide necessary assistance with daily tasks, such as using feeding tubes, wheelchairs, etc., to help patients better cope with their daily needs.

Assisted Breathing

As ALS progresses, patients may experience respiratory difficulties. Providing appropriate respiratory support, such as using a ventilator or oxygen device, can help patients maintain normal breathing function.

Nutrition and Eating

ALS patients may face swallowing difficulties that affect their nutritional intake. Providing suitable food states based on the condition, using feeding tubes or liquid nutritional supplements, can ensure that patients receive adequate nutrition.

Psychological and Emotional Support

The diagnosis and progression of ALS bring significant psychological and emotional stress to patients and their families. Offering psychological support, participating in relevant support groups, seeking professional counseling, etc., can help patients and their families cope with emotional challenges and enhance psychological resilience.

Safety Environment

Due to muscle weakness, ALS patients are prone to falling or losing balance. Providing a safe and comfortable environment, such as removing floor obstacles, installing handrails, using non-slip mats, etc., can reduce the risk of accidents.

Regular Monitoring and Treatment

ALS is a progressive disease, requiring regular monitoring and adjustments to the treatment plan to monitor disease progression and modify treatment approaches accordingly.

Reference

This article is provided for informational purposes only regarding industry information. The development of new drugs involves lengthy timelines, high financial investments, and is not guaranteed to be successful. These factors may expose investors to risks, and therefore, investors should exercise caution and prudence when making investment decisions.