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Supplements A Managed Care Perspective on Scientific Advances in Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis: Disease State Overview
Darrell Hulisz, PharmD, RPh
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Jordan Schultz, PharmD, MSCS, BCACP
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Disease-Modifying Treatment of Amyotrophic Lateral Sclerosis

Jordan Schultz, PharmD, MSCS, BCACP
Currently, there is no cure for amyotrophic lateral sclerosis (ALS) and the foundation of ALS management revolves around symptomatic and palliative care. Early diagnosis offers the best prognosis for a longer, quality life while living with the disease. Many medications are used to relieve symptoms but there are only 2 pharmacologic agents indicated for the management of ALS. For 2 decades, riluzole had been the mainstay of disease-modifying therapy, but in 2017, edaravone became the second agent approved in the management of patients with ALS. The mechanism of either agent is not well known. Riluzole is thought to reduce damage to motor neurons through an inhibitory effect on glutamate release, while edaravone is thought to act as a neuroprotective agent that prevents oxidative stress damage as a free radical scavenger. With the lack of treatment options, it is imperative for healthcare professionals to understand the nuances of using these 2 agents to optimize therapy and quality of life for patients with ALS.
Am J Manag Care. 2018;24:-S0
Amyotrophic lateral sclerosis (ALS) is a spectrum of neurodegenerative syndromes.1,2 Classical, or Charcot, ALS affects approximately two-thirds of patients and is characterized by deterioration of upper and lower motor neurons (UMNs and LMNs, respectively) of the spine, resulting in muscle spasticity, weakness, and wasting. Other motor system diseases include progressive bulbar palsy (PBP), affecting about a quarter of patients, progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

ALS is homogeneously spread throughout the world, with some areas of the western Pacific Rim experiencing locally increased incidence, such as specific people of Guam, Japan, and New Guinea.1 Men are slightly more likely to be affected than women (1.5:1), with a typical age of onset of 62 years.3 Just 5% of cases are diagnosed in patients younger than 30 years. Familial ALS is associated with earlier onset. Bulbar onset is more common in women and older patients (43% are aged more than 70 years). 

The natural course of the disease varies substantially between patients.4 ALS can progress at varying speeds, which may affect the timing of therapy and medical interventions. Approximately half of patients die within 30 months of symptom onset, whereas approximately 20% of patients survive between 5 and 10 years. Negative prognostic factors include bulbar and respiratory site of disease onset, executive dysfunction, and decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) prior to first evaluation.5

Multidisciplinary symptomatic and palliative care remains the cornerstone of ALS management.4 The management of the symptoms associated with ALS can be challenging. Patients with ALS may need physical, medical, and psychological interventions throughout the course of their disease. No cure exists for ALS and only 2 disease-modifying treatments have been approved in the United States: riluzole and edaravone. This article discusses the state of pharmacologic management of ALS, agents currently in development, and strategies for managing symptoms in patients with ALS.

Riluzole

Riluzole was approved in the United States in 1995 and the European Union in 1996.6 Riluzole extended the median time to tracheostomy or death of patients with ALS by 2 to 3 months in clinical trials.7 Riluzole is recommended for all patients with ALS; however, there are few data to indicate if it is effective in patients who had onset more than 5 years prior.8 Miller et al identified that riluzole provided a small beneficial effect on both bulbar and limb function, but not on muscle strength.9 Recently, Fang et al identified that riluzole may be most effective in the advanced respiratory stage of ALS in concert with findings by Seibold et al and Brooks et al.10-12

Proposed Mechanism of Action

Glutamate excitotoxicity has been proposed to contribute to ALS pathogenesis.13,14 Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Six different receptors bind glutamate to initiate an action potential. Of these, the N-methyl-d-aspartic acid (NMDA) receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lacking the GluR2 subunit allow the influx of calcium ions upon binding glutamate. Calcium ions entering the cell are sequestered in the endoplasmic reticulum (ER). Glutamate excitotoxicity occurs when glutamate in the local environment of these channels remains high, leading to excessive ion channel activity, calcium influx, damage to the ER, and neuronal death. The AMPA receptor lacking the GluR2 subunit is implicated in excitotoxic neuronal degeneration.

Clinical trials with riluzole were undertaken on the basis that riluzole may modulate glutamatergic transmission. However, trials with other targeted inhibitors of glutamatergic transmission (eg, ceftriaxone, memantine, and talampanel) have failed.6 Further, the accumulated data suggest that physiologically achievable levels of riluzole have only limited effects on glutamate receptors.6 Instead, it is becoming apparent that riluzole has many other actions on neurotransmitter function, including:
  • Modulation of persistent Na+ channel current
  • Potentiation of calcium-dependent K+ current
  • Inhibition of neurotransmitter release
  • Inhibition of fast Na+ current
  • Inhibition of voltage-gated Ca2+ current
  • Other possible effects on neurotransmission
Landmark Studies

Despite a poor understanding of the exact mechanism of action of riluzole in ALS, the drug received marketing authorization by the FDA based on the results of 2 trials.7,8,15 These studies were placebo-controlled, double-blind, international trials that included 1114 patients with probable or definite ALS for less than 5 years and a forced vital capacity (FVC) of greater than or equal to 60%. Patients received placebo or 50, 100, or 200 mg riluzole daily, split between morning and evening doses (Figure 1).6,13 The patients were evenly matched between groups, based on age; disease duration; body weight; respiratory, neurological, and muscle function; and clinician- and patient-assessed subjective status.

In the smaller study by Bensimon et al, the median time to death or tracheostomy was 83 days longer for patients receiving riluzole compared with placebo.7 There was an early increase in survival in patients receiving riluzole compared with placebo; however, by 15 months, the curves had almost merged. The survival differences were not statistically significant as determined by the planned statistical analysis, but a post hoc analysis demonstrated significant differences in survival between the riluzole and placebo groups.8

In the larger study by Lacomblez et al, the median time to death or tracheostomy was increased by 60 days (Figure 28).14,15 No initial increase in survival was seen in this study. As before, the survival differences were not statistically significant as determined by the planned statistical analysis, but a post hoc analysis demonstrated a significant effect of riluzole.8

After adjustment for prognostic factors, there was a significant overall drug effect at 12 and 18 months (Figure 3).15 At 18 months, the 50 mg, 100 mg, and 200 mg riluzole doses decreased the risk of death or tracheostomy compared with the placebo by 24% (P = .04), 35% (P = .002), and 39% (P = .0004), respectively.

Contrary to the study by Bensimon et al, Lacomblez et al did not observe difference in the treatment effect between groups based on different sites of disease onset (bulbar versus limb).7,15 Further, while riluzole improved survival (defined as time to death or tracheostomy) in both studies, preservation of muscle strength and neurological function was not seen in either study, despite improved bulbar and limb functional scores being found in the Cochrane meta-analysis of these clinical trials.9 However, asthenia and muscle relaxation are known effects of riluzole in healthy volunteers, and may mask neuroprotective effects in patients with ALS.15

Adverse Effects and Monitoring

Riluzole is relatively well tolerated. In a pooled analysis of safety data from patients receiving placebo (n = 320) or 100 mg/day riluzole (n = 313), the most common adverse effects (AEs) in the riluzole group (≥5% of patients and more frequently than in the placebo group) were asthenia, nausea, dizziness, decreased lung function, and abdominal pain.8 In many cases, the incidence of AEs with riluzole was only marginally higher than with placebo. The most common AEs leading to discontinuation in the riluzole group were nausea, abdominal pain, constipation, and elevated alanine aminotransferase (ALT).

Hepatotoxicity

Elevations in ALT were common. Approximately 50%, 8%, and 2% of the combined patients from both trials receiving riluzole experienced elevation of ALT level above normal, above 3 times the upper limit of normal (ULN), and above 5 times ULN, respectively.8 Maximum ALT levels typically occurred within 3 months after initiating riluzole. Patients should be monitored for hepatotoxicity monthly for the first 3 months, and periodically afterwards. Riluzole should be discontinued in patients whose ALT is greater than 5 times the ULN, or displaying other signs of hepatotoxicity (eg, elevated bilirubin). 

Neutropenia

Riluzole has immune-suppressive effects and can cause severe neutropenia (absolute neutrophil count <500/mm) within the first 2 months of treatment.8 Patients should be aware of the potential for febrile illnesses and report these occurrences promptly.

Pneumonitis

Interstitial lung disease, including hypersensitivity pneumonitis, may occur in patients receiving riluzole.8 Riluzole should be discontinued if interstitial lung disease develops.

Pharmacokinetic considerations

Riluzole is metabolized extensively in the liver, primarily by CYP1A2.8,16 The use of CYP1A2 inhibitors and inducers should be undertaken cautiously. Compared with healthy volunteers, mild and moderate chronic hepatic impairment reduces clearance (increases the area under the curve [AUC]) of riluzole by approximately 1.7-fold and 3-fold. Other factors that reduce riluzole clearance include Japanese descent (~50%), female gender (~45%), and smokers (~20%). On the other hand, a high-fat meal and smoking increases clearance (reduces AUC) by approximately 20% each.

Recommendations for Use

Riluzole should be recommended for all patients with ALS, provided there are no contraindications to its use. Riluzole is recommended by the European Federation of Neurological Societies (EFNS), American Academy of Neurology (AAN), and other neurological guidelines.17,18 Riluzole is recommended for patients with ALS of less than 5 years’ duration and FVC  greater than 60%. However, many experts suggest that riluzole has potential benefit for the prevention of aspiration in those patients with symptoms more than 5 years, FVC less than 60%, and tracheostomy.17

Based on the landmark studies, and 2 other controlled studies, riluzole prolongs survival by approximately 2 to 3 months. However, other uncontrolled studies, having longer follow-up periods, suggest that survival may be prolonged by up to 21 months.17 

The typical dose of riluzole is 100 mg/day, orally divided in 2 separate doses of 50 mg.8 This dose was deemed a good balance between efficacy and risk of AEs.15 At lower doses, treatment discontinuation was primarily due to lack of efficacy, while at higher doses, it was due to toxicity. Oral availability is approximately 60%.

 
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