Amyotrophic Lateral Sclerosis (ALS): Recent Advances and Management Strategies

The approval of new treatment options for ALS means that payer strategy will become more important to proper management.

A progressive, disabling, and fatal neurodegenerative disorder, amyotrophic lateral sclerosis (ALS) affects motor neurons in the brain and spinal cord that control voluntary muscle movement in the body.1,2 Up to 30,000 adults in the U.S. are living with ALS, with an estimated 5,000 new cases diagnosed yearly.1 ALS is most common in adults over age 60.1 ALS is diagnosed based on a review of symptom history coupled with a physical exam; often, a series of tests are utilized to rule out other diseases with similar symptom presentation.2 While the cause of ALS is unknown, some studies suggest genetics and environmental factors may contribute.2

John Joffer, Pharm.D. Vice President, Pharmacy Services PacificSource

Early stage ALS manifests as muscle twitching and cramping, loss of muscle control and muscle weakness and fatigue; it affects muscles such as the arms, legs, shoulders, neck, and diaphragm. As a result, patients with ALS are initially likely to trip and fall, drop things, have slurred or thick speech, and have difficulty projecting their voice.2 As ALS progresses, the severity of symptoms increases and patients go on to experience shortness of breath, difficulty breathing, difficulty chewing and swallowing, and paralysis.2 Disease progression is measured using the ALS Functioning Rating Scale (ALSFRS-R); a substantial decline in functioning is reflected by point decreases in the ALSFRS-R.4

In the U.S., total costs associated with ALS are $212 million to $1.4 billion per year, including direct and indirect costs to this population.5 The average anticipated cost of care per patient varies in the U.S. from $16,000 to $200,000, depending on the stage of the disease.3

Current Treatment Landscape

The first treatment available indicated for ALS, riluzole (RILUTEK®), was approved by the U.S. Food & Drug Administration (FDA) in 1995.6 The second FDA-approved drug for ALS, edaravone (RADICAVA®), was approved in 2017.7 The American Academy of Neurology (AAN) Treatment Guidelines from 2009, which have been most recently reaffirmed in February 2023, recommend riluzole for the treatment of ALS. The guidelines are silent on more recently approved treatments, including edaravone, taurursodiol, and tofersen.8 As the treatment landscape continues to expand, updated guidelines and real-world evidence will be critical in providing clear guidance around appropriate management and consensus-driven place in therapy for these treatments.

Recent Approvals

Edaravone (RADICAVA ORS®)

The FDA approved an oral suspension form of edaravone (RADICAVA ORS®, Mitsubishi Tanabe Pharma) in May 2022 for the treatment of ALS.9 Edaravone was originally approved in 2017 as an intravenous (IV) infusion after efficacy for the treatment of ALS was demonstrated in a six-month clinical trial. The effectiveness and approval of the oral suspension was then based on the study results showing comparable levels of oral edaravone in the bloodstream to levels from the IV formulation.9 Common side effects associated with edaravone are bruising, problems walking, headaches, and possibly fatigue.9

Sodium phenylbutyrate; taurursodiol (RELYVRIO®)

In September 2022, the FDA approved sodium phenylbutyrate/ taurursodiol (RELYVRIO®, Amylyx Pharmaceuticals) to treat ALS through priority review and orphan drug pathways.10 Sodium phenylbutyrate/taurursodiol can be taken orally before a snack or meal and also administered via feeding tube; before administration, one packet should be combined in 8 ounces of room temperature water.10 The recommended dose is one packet daily for the first three weeks followed by one packet twice daily thereafter.10

Efficacy was evaluated and demonstrated in a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study that included 137 adult patients with ALS who were randomized to receive either sodium phenylbutyrate/ taurursodiol or placebo.11 Patients treated with sodium phenylbutyrate/taurursodiol were shown to experience a slower rate of decline in the study’s clinical assessment of daily functioning compared to those receiving a placebo;11 a post hoc, long-term analysis demonstrated longer overall survival in patients who originally received sodium phenylbutyrate/ taurursodiol versus placebo.12 Adverse reactions associated with treatment were diarrhea, abdominal pain, nausea, and upper respiratory tract infection.10 Notably, taurursodiol, a bile acid, may cause worsening diarrhea in patients with disorders that interfere with bile acid circulation.10

Tofersen (QALSODY®)

The FDA approved tofersen (QALSODY®, Biogen) in April 2023 for the treatment of ALS. The recommended dose of tofersen is 100 mg administered intrathecally by a healthcare professional.13 Three initial doses are administered at 14-day intervals, followed by a maintenance dose every 28 days.13 Approval was based on results from a 28-week, randomized, double-blind, placebo-controlled clinical study in 147 patients with weakness attributed to ALS and a confirmed superoxide dismutase 1 gene (SOD1)-mutation.14 In this study, 108 patients were randomized to receive treatment with either tofersen or placebo for 24 weeks.14 Treatment with tofersen was associated with nominally significant reductions in plasma neurofilament light (NfL) concentration at week 28 compared to treatment with placebo.14 The FDA determined that the results are reasonably likely to predict a clinical benefit in patients.

Tofersen was approved under the accelerated approval pathway. To further support clinical benefit, there is an active phase 3 randomized, double-blind, placebo-controlled trial in individuals who are carriers of the SOD1 genetic mutation who do not yet have symptoms.13 This study will assess and compare the development of ALS symptoms in individuals treated with tofersen and placebo.13 Treatment with tofersen was associated with side effects including pain, fatigue, arthralgia, increased cerebrospinal fluid, white blood cells, and myalgia.13

ICER Review

An Institute of Clinical and Economic Review (ICER) report from September 2022 included an analysis on the cost of ALS therapies, specifically edaravone and sodium phenylbutyrate/taurursodiol.15 The report noted that edaravone provided an added 0.04 qualityadjusted life years (QALYs) and 0.05 equal value life years gained (evLYG) compared with standard care.15 Edaravone was deemed not cost-effective at its list price of $171,000 per year. It was also noted that patients gained 0.14 QALYs and 0.31 evLYGs with sodium phenylbutyrate/taurursodiol added to standard care of therapies; however, this therapy was also found to be not cost-effective at the placeholder price used for the analysis ($169,000 per year).15 The list price of sodium phenylbutyrate/taurursodiol, now available, is $158,000 per year.15 An ICER determination of cost effectiveness at this list price has not yet been published.

Managed Care Impact

Management of ALS requires multidisciplinary teams comprised of a combination of healthcare professionals: physicians, pharmacists, physical, occupational and speech therapists, nutritionists, social workers, respiratory therapists, clinical psychologists, and home care and hospice nurses.2 Proper treatment may include medication paired with physical therapy, speech therapy, nutritional support, and respiratory support. Since ALS management is patient-specific, a patient’s treatment team can be crucial in tailoring an individualized treatment plan.2 Coordination between managed care organizations and the care team will be key to appropriate management, optimizing outcomes, and potentially delaying disease progression.16

With the approval of new treatment options for ALS, payer strategy around this category will become more important to proper management. Payers may benefit from strategizing how they can best manage the space while ensuring patients have access to the most appropriate therapy, particularly now that there are several available options. Utilization management by managed care organizations and payers as well as support for the multidisciplinary care teams may lead to improved outcomes and better cost management.16

References

1. “ALS – amyotrophic lateral sclerosis.” Johns Hopkins Medicine, https://www.hopkinsmedicine.org/neurology_neurosurgery/ centers_clinics/als/conditions/als_amyotrophic_lateral_sclerosis. html.

2. “Amyotrophic Lateral Sclerosis (ALS) Fact Sheet.” National Institute of Neurological Disorders and Stroke, 22 Jun. 2020, https://www. ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/ Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet.

3. Santaniello, B. “ALS Managed Care Considerations.” American Journal of Managed Care. https://www.ajmc.com/view/als-managedcare-considerations.

4. Berry, James D., et al. “The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical trials.” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 23 Oct 2012, https://www.tandfonline.com/doi/full/10.3109/21678421.2012.7 62930

5. Berry, James D., et al. “Epidemiology and economic burden of amyotrophic lateral sclerosis in the United States: a literature review.” Amyotrophic Lateral Sclerosis Frontotemporal Degeneration, 7 Feb. 2023, https://pubmed.ncbi.nlm.nih.gov/36748473.

6. Miller, R.G., et al. “Clinical trials of riluzole in patients with ALS. ALS/ riluzole study group – II.” Neurology, 1996, https://pubmed.ncbi. nlm.nih.gov/8858057/.

7. “FDA approves drug to treat ALS.” U.S. Food & Drug Administration, 5 May 2017, https://www.fda.gov/news-events/pressannouncements/fda-approves-drug-treat-als.

8. “AAN Summary of Evidence-based Guideline for CLINICIANS: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional and respiratory therapies.” American Academy of Neurology, 11 Jan. 2020, https://www.aan.com/Guidelines/home/ GuidelineDetail/370.

9. “FDA Approves Oral Form for the treatment of adults with amyotrophic lateral sclerosis (ALS).” U.S. Food & Drug Administration, 12 May 2022, https://www.fda.gov/drugs/news-events-humandrugs/fda-approves-oral-form-treatment-adults-amyotrophiclateral-sclerosis-als.

10. “FDA Approves New Treatment Option for Patients with ALS.” U.S. Food & Drug Administration, 29 Sept. 2022, https://www.fda.gov/ news-events/press-announcements/fda-approves-new-treatmentoption-patients-als.

11. Paganoni, Sabrina, et al. “Trial of Sodium PhenylbutyrateTaurursodiol for Amyotrophic Lateral Sclerosis.” The New England Journal of Medicine, 3 Sept. 2020, https://pubmed.ncbi.nlm.nih. gov/32877582/.

12. Paganoni, Sabrina, et al. “Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes.” Muscle Nerve, Aug. 2022, https://pubmed. ncbi.nlm.nih.gov/35508892/.

13. “FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene.” U.S. Food & Drug Administration, 25 Apr. 2023, https://www.fda.gov/drugs/newsevents-human-drugs/fda-approves-treatment-amyotrophic-lateralsclerosis-associated-mutation-sod1-gene.

14. Miller, Timothy M., et al. “Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.” The New England Journal of Medicine, 22 Sept. 2022, https://www.nejm.org/doi/10.1056/NEJMoa2204705.

15. “ICER Publishes Final Evidence Report and Policy Recommendations on Treatments for Amyotrophic Lateral Sclerosis.” Institute for Clinical and Economic Review, 13 Sept. 2022, https://icer.org/news-insights/ press-releases/icer-publishes-final-evidence-report-and-policyrecommendations-on-treatments-foramyotrophic-lateral-sclerosis/.

16. Wong, Winston. “The Role of Managed Care Professionals in Improving Care for Patients with ALS.” American Journal of Managed Care, 17 Aug. 2020, https://www.ajmc.com/view/the-role-ofmanaged-care-professionals-in-improving-care-for-patients-with-als.