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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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Disease-Modifying Treatment of Amyotrophic Lateral Sclerosis
Jordan Schultz, PharmD, MSCS, BCACP
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Disease-Modifying Treatment of Amyotrophic Lateral Sclerosis

Jordan Schultz, PharmD, MSCS, BCACP
Summary of Riluzole
  • Mechanism of action: inhibits glutamate excitotoxicity; other undefined neuroprotective actions13,14
  • Efficacy: prolongs median time to death or tracheostomy by 2 to 3 months7
  • Safety: relatively well tolerated; most common AEs are asthenia, nausea, dizziness, decreased lung function, and abdominal pain; some patients may experience hepatotoxicity, neutropenia, or interstitial lung disease8
  • Dosing: 100 mg/day; racial, gender, and individual metabolic variations may lead to differences in AUC and enhanced toxicity8
  • Other considerations: susceptible to variable pharmacokinetics due to presystemic and systemic metabolism8,16

Edaravone is an antioxidant and free radical scavenger that was initially developed as an intravenous (IV) treatment of acute ischemic stroke.19 Despite mixed clinical results, it was approved by the FDA in May 2017.20

Proposed Mechanism of Action

Excessive production and inefficient neutralization of reactive oxygen species (ROS) leads to oxidative stress and cell death. Endogenous ROS are produced during normal metabolism in mitochondria and may increase during times of stress to cells.21 During oxidative phosphorylation in mitochondria, electrons pass through the electron transport chain to power the electrochemical proton gradient that is used to produce adenosine triphosphate. The terminal receptor of the electron is oxygen, which is reduced to water. However, a small amount of oxygen, after receiving an electron, escapes as a free radical species. ROS can attack, destroy, and inactivate all manners of intracellular molecules (eg, proteins, lipids, nucleic acids). Buildup of these products leads to the activation of apoptotic cell death. Cells have developed multiple mechanisms to neutralize ROS before cell death is initiated. Superoxide dismutase, catalase, and the glutathione pathway are major pathways to neutralize ROS and repair the damage caused by ROS.

At least 25 genes have been implicated in ALS pathogenesis, of which SOD1 was the first to be described. The primary function of SOD1 is to neutralize superoxide radicals (O2●‒) by reacting with water to form O2 and H2O2. However, mutations in the SOD1 gene may lead to neuron death and ALS via the following mechanisms:
  • Increased aggregation
  • Dimer destabilization
  • Aberrant metal binding
  • Oligomerization22
The most common mutations found in the human SOD1 gene are:
  • D90A (most common mutation in the US population, but may not be associated with ALS)23
  • A4V (responsible for approximately 50% of SOD1 mutations associated with familial ALS in North America)24
  • G93A (rare mutation, although very well characterized, as it can generate motor neuron syndrome in transgenic mice)22
Although SOD1 mutations help highlight the importance of ROS in the pathology of ALS, just about 20% of ALS cases are associated with a mutation of the SOD1 gene. Therefore, it is unclear why patients with sporadic ALS have increased ROS levels or why they are more susceptible to oxidative stress. Regardless, increased ROS levels are thought to be a primary pathological feature of ALS and edaravone aims to reduce oxidative stress.

Landmark Studies

It took more than 13 years to bring edaravone through the clinical development process on the way to approval.25 The first open-label study recruited 19 Japanese patients to receive 30 mg or 60 mg of edaravone IV daily on a schedule of 14 days on, followed by 14 days off.26 The primary end point of this study was the change in the ALSFRS-R in the 6 months before treatment compared with changes observed following 6 months of treatment. In contrast, the primary end point of the riluzole studies was survival or time to tracheostomy. A statistically significant treatment effect was observed on the primary end point in the high-dose group (2.4 ± 3.5 points; P = .039).27,28

Subsequently, 2 phase 3 studies were conducted. One study recruited 206 patients and the other recruited 25 Japanese patients with an FVC greater than 70%, disease duration less than 3 years, and a decrease in the ALSFRS-R score during the 12-week preobservation period of 1 to 4 points, and used the same endpoint of change in ALSFRS-R score.29,30 Neither demonstrated an improvement in symptom control with edaravone. However, a post hoc analysis was conducted on patients who had a score of 2 or more on each item of the ALSFRS-R, disease duration of 2 years or less, and an FVC of at least 80% at baseline. This subset of patients represents a group that may be more prone to disease progression. Within this subgroup of patients, those taking edaravone had a significantly slower rate of progression of the ALSFRS-R compared with the placebo group.

Based on the post hoc analysis described above, a third confirmatory phase 3 study was conducted.19 The recruitment strategy for this study was stringent and based on the previously described post hoc analysis and included patients with the following:
  • Definite or probable ALS
  • Disease duration 2 years or less
  • Normal respiratory function (FVC ≥80%)
  • High functionality (defined as scores of ≥2 points on each individual item of the ALSFRS-R)
Of 213 screened patients, 137 completed the 12-week prerandomization observation period, during which they experienced a 1–4-point decrease in ALSFRS-R score, as in the previous trials. Patients were randomized to edaravone (60 mg IV) or saline placebo (Figure 4).25 The primary endpoint was, again, change in ALSFRS-R score.

There were more women in the edaravone group (45% vs 40%, placebo) and more patients with grade 1 disease in the edaravone group (32% vs 24%, placebo). Other than that, patient cohorts were evenly matched for age, body mass index, ALS diagnosis, bulbar versus limb onset, decrease in ALSFRS-R score during observation, and prior riluzole use.

The primary endpoint analysis included all randomly assigned patients who received at least 1 dose of study drug, had at least 1 efficacy assessment post baseline, and reached the end of cycle 3.19 Sixty-eight patients receiving edaravone reached cycle 6, while 66 patients receiving placebo reached the same point. For the primary efficacy analysis, the change from baseline to the end of cycle 6 (or last observation) in ALSFRS-R score was compared between treatment groups. The least-squares mean difference in mean ALSFRS-R scores between treatment groups was 2.49 in favor of edaravone (95% CI, 0.99-3.98, P = .0013; Table 1).25

Patients receiving edaravone maintained higher scores on the Modified Norris Scale, which describes speech, swallowing, and lower extremity and upper extremity abilities, compared with placebo.19 However, deterioration in quality of life, as measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), was slightly, but statistically significantly, lower in patients receiving edaravone compared with patients receiving placebo (P = .031). There was no difference in FVC, subsets of Modified Norris Scale, grip strength, pinch strength, or ALS severity classification at the end of cycle 6 in patients receiving edaravone, compared with placebo.

AEs and Monitoring

The safety profile of edaravone is favorable. During the trial, 84% of patients in each arm experienced an AE, with 16% of patients receiving edaravone and 24% of those receiving placebo experiencing a serious AE (Table 2).19 The most common AE was contusion (19% edaravone, 13% placebo).

Pharmacokinetic Considerations

No changes in dosing are needed for patients with hepatic or renal insufficiencies.31 Edaravone contains sodium bisulfite, which may cause allergic reactions in some people. Edaravone is metabolized to a pharmacologically inactive form that is excreted in the urine. Edaravone is not believed to have significant interactions with CYP enzymes. Differences in pharmacokinetics between Japanese and Caucasian subjects were not seen. Lastly, high systemic levels of edaravone are achievable and may drive brain penetration.16

Recommendations for Use

While edaravone should be recommended to all patients with ALS, there are many considerations for which we do not have enough data or experience to guide us. For the trial that was used to support approval, the selection criteria were strict: just about 7% of patients with ALS would have qualified for the trial.32 Nevertheless, it is assumed that edaravone has applicability in patients who fall outside of these narrow criteria. This trial was also of short duration (6 months) and it is unclear as to the long-term outcomes with edaravone. Improved functional scores were seen, but long-term survival data are lacking. The current recommendations do not differentiate patient subsets that might have benefit from edaravone therapy, because this trial was not powered to identify those differences. The patients in this trial appeared to have disease that was likely to progress, and the utility of edaravone in patients with slower progressing disease has not been evaluated.

Patients should be educated about the potential benefits versus the costs.32 “Costs,” in this case, should also include time and energy that is required to remain adherent to this dosing strategy. Dosing can be cumbersome, requiring IV administration for 10 of 14 days per 28-day cycle. Initial cycle is 14 days on, then 14 days off. Subsequent cycles are 10 of 14 days on, then 14 days off. The monetary cost is quite high. The cost for edaravone is about  $1000 per treatment, which translates to a cost of almost $146,000 per year.33

Summary of Edaravone
  • Mechanism of action: antioxidant and free radical scavenger19
  • Efficacy: improves functional score, but long-term survival data are not fully evaluated32
  • Safety: relatively well tolerated; most common AEs are contusion, gait disturbance, headache, dermatitis19
  • Dosing: Initial cycle: 60 mg/day IV for
  • 14 days followed by 14 days without drug. Subsequent cycles: 60 mg/day IV for 10 of 14 days, followed by 14 days without drug31
  • Other considerations: pharmacokinetics less variable than riluzole; high cost (>$145,000/year)31,33
Symptomatic Therapies

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