CADTH Horizon Scan

Emerging Drugs for Amyotrophic Lateral Sclerosis

Emerging Health Technologies

Authors: Michel Boucher, Monika Mierzwinski-Urban

Key Messages

• Horizon scan reports provide brief summaries of information regarding new and emerging health technologies. These technologies are identified through the CADTH Horizon Scanning Service as topics of potential interest to health care decision-makers in Canada. This Horizon Scan summarizes the available information regarding emerging drug therapies for the treatment of patients with amyotrophic lateral sclerosis.

• Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disorder characterized by muscle weakness and wasting. ALS can be classified as sporadic (sALS), which accounts for 85% to 90% of the cases, or familial (fALS), which includes 10% to 15% of the cases.

• At present, 2 drugs are available in Canada for the treatment of patients with ALS, riluzole and edaravone. These 2 drugs provide modest benefits in terms of survival and function.

• Many treatments are currently in various stages of clinical development. Fasudil, Ibudilast, inosine, and masitinib are drugs of interest as they have completed phase II, and some have initiated phase III, of their respective clinical development. Several other drugs are in clinical development and are briefly described in this report: AT-1501, CNM-Au8, engensis, pridopidine, verdiperstat, and zilucoplan.

• Emerging drugs for ALS pertain to different drug classes. Despite different mechanisms of action, these drugs all aim at providing a neuroprotective effect that will result in slowing of disease progression, maintenance of patient functional status, and improvement in patient survival.

• Of the 4 ALS drugs of interest in late-stage development, fasudil, ibudilast, and inosine have completed phase II of clinical development.

• The estimated completion date for phase III of clinical development for masitinib is December 2022.

Methods

These bulletins are not systematic reviews and do not involve critical appraisal or include a detailed summary of study findings. Rather, they present an overview of the technology and available evidence. They are not intended to provide recommendations for or against a particular technology.

Literature Search Strategy

A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology (HTA) agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were amyotrophic lateral sclerosis (ALS) and inosine, masitinib, EH301, nicotinamide and pterostilbene, pterostilbene, AT-1501, engensis, fasudil, ibudilast, zilucoplan, verdiperstat, CNM-Au8, pridopidine (Table 1). No filters were applied to limit the retrieval by study type. The search was also not limited by language or by publication year. Regular alerts updated the search until project completion; only citations retrieved before December 1, 2021, were incorporated into the analysis.

Study Selection

One author screened the literature search results and reviewed the full text of all potentially relevant studies. Studies were considered for inclusion if the intervention was 1 of the drugs listed in Table 1. Conference abstracts and grey literature were included when they provided additional information to available published studies.

Peer Review

A draft version of this bulletin was reviewed by a clinical expert. The manufacturers were also given the opportunity to comment on an earlier draft.

Background

ALS, also known as Lou Gehrig’s disease and motor neuron disease,^1,2 is a progressive fatal neurodegenerative disorder.^3,4 In 70% of patients, ALS is characterized by limb-onset (initial weakness and wasting of arm or leg muscles); whereas 25% of patients have bulbar-onset (initial difficulty swallowing and slurring of speech), and the remaining patients (5%) have trunk-onset (respiratory involvement).^3,4 Sporadic ALS (sALS) often occurs in those with no family history and accounts for 85% to 90% of the cases. Familial ALS (fALS) occurs when at least 2 persons of the same family are diagnosed and accounts for 10% to 15% of ALS cases.⁴ The lack of difference in the clinical symptoms between sALS and fALS patients may indicate a common molecular mechanism as the basis of this disease.⁴

ALS diagnosis is based on medical history, physical examination, electro-diagnostic testing, and neuroimaging studies. ALS may be difficult to differentiate from other conditions such as myasthenia gravis or multiple sclerosis.¹ The time from symptom onset to ALS diagnosis can vary from 9 to 12 months⁵ or in some cases up to 24 months.⁶

In Canada, it is estimated that about 3,000 persons are currently living with ALS.⁷ A meta-analysis has estimated the pooled ALS annual standardized incidence for Europe, New Zealand and North America to be 1.81 of 100,000.⁸ Studies have estimated the prevalence of ALS to be 4.1 to 8.4 per 100,000 persons.⁶ Commonly cited estimates of the global prevalence of ALS vary between 200,000² and 235,000 persons,⁹ though estimates as low as 55,000¹⁰ and as high as 500,000 persons¹¹ have also been reported. There is a projected 69% increase in the prevalence of this condition by year 2040.⁹

The mean age of onset of symptoms is 58 years to 63 years for sALS and 40 years to 60 years for fALS.³ Men have a higher risk of sALS with limb-onset than women (global sex ratio of 1.2 to 1.5).³ Prognosis is poor; the mean survival time from symptom onset to death or invasive respiratory support is between 24 months and 50 months.⁶ Some patients (about 10%) will have a survival of 10 years or longer.⁶

It is generally accepted that both genetic and non-genetic factors play a role in the pathogenesis of ALS.⁴ Non-genetic risk factors for ALS include being male and older age.^3,6 Other possible risk factors include smoking, body mass index, physical inactivity, exposures to metals, pesticides, b-methylamino-L-alanine, head injury, and viral infections.³ At least 20 gene mutations have been implicated in ALS, including mutations in superoxide dismutase 1 (SOD1)(15% to 20% of fALS and 3% of sALS), TAR DNA binding protein (4% of fALS and 1% of sALS), and C9orf72 (5% of sALS and 30% of fALS).⁴

There is no cure for ALS.¹ Clinical management of ALS includes symptom, respiratory, and nutritional management.¹ Two drugs, riluzole and edaravone, are available in Canada for the treatment of ALS and may provide modest benefits.⁷ Riluzole may delay time to death or time to tracheostomy by approximately 3 months. Edaravone may delay functional decline, particularly when the treatment is initiated in patients with early disease.¹² As there is a need for improved therapeutics for patients with ALS, many drug treatments are in clinical development.^13,14,12,15 The purpose of this report is to provide an overview of emerging drug molecules that are currently in advanced clinical development. Of note, the combination of sodium phenylbutyrate and taurursodiol (also known as tauroursodeoxycholic acid or AMX0035) is currently under review by CADTH and will therefore not be reviewed in this report.

The Technologies

A total of 11 drugs were initially identified and included in the literature search (Table 1). Table 2 provides a short description of the mechanism of action of 4 identified drugs of interest. Drugs that have not completed phase II of their clinical development were excluded from the main review and are discussed in the Concurrent Development section and Appendix 1.

Regulatory Status

Drugs described in Table 2 are not currently available in Canada. Of interest, in 2018 the Committee for Medicinal Products for Human Use of the European Medicine Agency (EMA) recommended the refusal of the marketing authorization for Alsitek (masitinib) for the treatment of ALS since masitinib was deemed not effective at slowing disease progression based on interim results from phase II/III study AB10015.²² Final results⁹ as well as new overall survival data from this study have since become available.²³ In addition, a phase III clinical trial of masitinib for the treatment of patients with ALS, in combination with riluzole, was targeted for completion in December 2022.²⁴ However, masitinib’s development was temporarily halted in 2021 due to safety concerns.^25,26

Cost

There is no cost information currently available.

Target Population

The population targeted for the use of the new emerging drugs described in this report is adults with ALS, which includes approximately 3,000 persons in Canada.⁷

Current Practice

While there are no formal ALS clinical practice guidelines in Canada, the first Canadian Best Practice Recommendations on the Management of ALS were recently developed.⁷ Reflecting the multiple needs of patients with ALS, these recommendations cover a broad range of topics including, the communication of the diagnosis of ALS, the use of disease-modifying therapies (riluzole and edaravone), and the need for patients to access multidisciplinary clinics. Other key aspects include nutritional interventions (e.g., enteral tube insertion) and respiratory care, in particular the use of non-invasive ventilation. The management of symptoms is also important, in particular the need to assess pain regularly and tailor pain control interventions toward the multiple specific causes of pain.⁷

Two drugs are presently available in Canada; riluzole and edaravone.⁷ They provide modest benefits in terms of survival (riluzole) and function (edaravone).¹² Riluzole is administered orally twice daily. It may extend survival and/or time to tracheostomy in some patients with ALS. There is no evidence that riluzole exerts a therapeutic effect on motor function, lung function, fasciculations, muscle strength and motor symptoms; the drug has not been shown to be effective in the late stage of ALS.²⁷ Edaravone is indicated to slow the loss of function in patients with ALS, as measured by the ALSFRS-R scale. Edaravone is administered IV as a 1-hour infusion following a schedule involving an initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles are administered daily for 10 days out of 14-day periods, followed by 14-day drug-free periods.²⁸ Of note, an oral formulation of edaravone is being developed and is soon expected to complete its phase III clinical development.²⁹

Summary of the Evidence

Evidence currently available on emerging drugs of interest to this report initially included 26 relevant publications retrieved through the literature search. Among these, there were 17 conference abstracts and 9 full-text articles. Full-text articles report results from 7 trials, 2 sets of case reports, and 1 study protocol. Table 3 describes the number of, and type of publications retrieved for each of the 11 emerging drugs that were initially of interest and the inclusion, or exclusion, of publications based on the selection criteria. After further screening the publications retrieved, 13 conference abstracts and 6 full-text articles were included. Early emergent drugs without completed phase II trials or higher are excluded and discussed in the Concurrent Development section and in Appendix 1.

Fasudil

There are 2 registered clinical trials of fasudil for the treatment of patients with ALS. The first 1, completed in May 2015, was a phase II open-label, single-centre, clinical trial. The control group was composed of placebo patients from historical research (NCT01935518).⁵⁵ Results were presented in the form of an abstract at the 26th International Symposium on ALS/Motor Neuron Disease.³⁰ The objective was to determine whether fasudil is effective and safe in treating patients with ALS. The key study entry criteria included a clinical diagnosis of laboratory-supported probable, probable, or definite ALS; disease duration of 3 to 36 months; forced vital capacity (FVC) of at least 60% of predicted, and an Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score of at least 30 (respiratory items: at least 10) with decline in the 3 months preceding enrolment varying from 1 to 8. Patients also had to be taking riluzole.^55,30 Of note, ALSFRS-R is a validated rating scale that measures the global function of patients with ALS. The total score varies from 0 (worst) to 48 (best).⁵¹ During the study, all patients were treated with IV fasudil 30 mg twice a day for 14 days; this treatment was repeated 3 months later. The primary and secondary outcome measures were the slope of decline of the ALSFRS-R score and survival time. Safety was assessed throughout the trial. Ten patients were enrolled; 9 completed the treatment. There were no treatment-related severe adverse events (AEs) during the 6-month follow-up period. Compared with 18 matched (historical) controls, there was no difference (P = 0.263) in the decline of the ALSFRS-R score in the fasudil group during the first 3 months; the decline was greater in the fasudil group during the second 3 months (P = 0.008). There was no between-group difference in the survival time observed during the 6-month follow-up period (no P value reported).³⁰

The second study (ROCK-ALS; NCT03792490) is an ongoing phase IIa, multi-centre, randomized, double-blind, placebo-controlled trial assessing the safety, tolerability, and efficacy of fasudil administered IV in 2 different doses, 30 mg/day and 60 mg/day. It targets enrolling 120 patients (80 patients on fasudil and 40 patients on placebo); these patients will come from approximately 16 trial sites located in Germany, France, and Switzerland. The estimated study completion date is July 2022.¹⁶ Three case reports of the compassionate use of fasudil in patients with ALS were also recently published.³¹

Ibudilast (MN-166)

There are 2 relevant clinical trials for ibudilast. The first is a phase II single-centre, randomized, double-blind, placebo-controlled trial (IBU-ALS-1201; NCT02238626). Randomization followed a 2:1 ratio (ibudilast: placebo). The double-blind component lasted 6 months; it was followed by a 6-month open-label phase (for placebo patients only). The study evaluated the safety, tolerability, and clinical responsiveness of ibudilast, as add-on therapy in 60 patients with ALS. Ibudilast was administered at a daily dose of 60 mg; patients were also using riluzole (100 mg per day). The study was completed in December 2017; results were taken from the National Institute of Health (NIH) trial registry .¹⁸ Although it initially aimed at enrolling 60 patients, a total of 70 patients participated. Patients were divided into early ALS (ibudilast = 34; placebo = 17) and advanced ALS cohorts (ibudilast = 11; placebo n = 8). The primary outcome was safety, assessed by monitoring and recording all treatment emergent AEs (TEAEs), including serious AEs and discontinuations due to treatment emergent AEs that occurred over 6 months. All patients in each group reported AEs.¹⁸ Serious AEs were reported as follows:

• Early ALS cohort: placebo = 1 of 17 (5.9%); ibudilast = 5 of 34 (14.7%)

• Advanced ALS cohort: placebo = 2 of 8 (25.0%); ibudilast = 3 of 11 (27.3%).¹⁸

There were several secondary outcomes measured over the 6-month observation period of the trial. Results of key secondary outcomes are presented below (no P value reported).¹⁸

• Mean change in ALSFRS-R total score from baseline to month 6 (mean, standard deviation [SD])

  • Early ALS cohort: placebo = −3.8 (3.9); ibudilast = −4.5 (5.1)

  • Advanced ALS cohort: placebo = −2.2 (2.6); ibudilast = −4.8 (4.9).¹⁸

• Change in respiratory function (breathing capacity) from baseline to month 6, as measured by slow vital capacity (mean, SD):

  • Early ALS cohort: placebo = −6.1 (9.3); ibudilast = −10.1 (9.9)

  • Advanced ALS cohort: placebo = −12.2 (7.1); ibudilast = −11.1 (18.7).¹⁸

• Muscle strength measured by manual muscle testing and instrumented hand-held dynamometry (mean, SD):

  • Early ALS cohort: placebo = −3.9 (5.4); ibudilast = −4.9 (5.5)

  • Advanced ALS cohort: placebo = −1.3 (2.4); ibudilast = −4.4 (3.6).¹⁸

• Change in quality of life as measured by the Amyotrophic Lateral Sclerosis Assessment Questionnaire — 5 (mean, SD):

  • Early ALS cohort: placebo = 2.1 (3.0); ibudilast = 1.6 (2.8)

  • Advanced ALS cohort: placebo = −0.7 (2.1); ibudilast = 4.8 (3.6).¹⁸

• Clinical Global Impression of Change (mean, SD):

  • Early ALS cohort: placebo = −1.0 (0.8); ibudilast = −1.4 (0.8)

  • Advanced ALS cohort: placebo = −1.3 (0.5); ibudilast = −1.6 (0.7).¹⁸

The second study of interest is an ongoing phase IIb/III multi-centre, randomized, double-blind, placebo-controlled, parallel-group clinical trial (COMBAT-ALS, NCT04057898). This study aims to evaluate the efficacy, safety, and tolerability of ibudilast administered at a daily dose of 100 mg during 12 months to patients with ALS. This study part will be followed by a 6-month, open-label, extension phase. The estimated completion date of this trial is December 2024.⁵⁶

Inosine

A multi-centre phase II trial was conducted (SURE-ALS2, NCT03168711).⁵⁷ This randomized, placebo-controlled trial was completed in January 2020; results are not published but are available on the NIH trial registry.⁵⁷ The primary objective of the SURE-ALS2 study was to determine the safety and tolerability of daily orally administered inosine. Dosing was selected to moderately elevate serum urate levels over 20 weeks. The primary end points were the number of participants with AEs and tolerability which was defined as the number of participants able to complete the 20-week study without permanently discontinuing the study drug or suspending the study drug for greater than 28 days. Adult patients (ages 18 to 85) were recruited from 3 US ALS centres. Key inclusion criteria included sALS or fALS diagnosed as possible, laboratory-supported probable, probable, or definite disease as defined by revised El Escorial criteria, slow vital capacity ≥ 60% at the screening visit, and serum urate < 5.5 mg/dL at screening (i.e., below the population median serum urate levels). The study aimed at enrolling 48 patients but only 23 initiated treatments, 14 patients in the inosine group and 9 patients in the placebo group. Of these, 19 completed the study, 12 patients in the inosine group and 7 patients in the control group.⁵⁷ Results reported are as follows (no P value reported):

• All-cause mortality: inosine: 0 of 14 (0.0%); placebo: 1 of 9 (11.1%)

• Serious AEs: inosine: 4 of 14 (28.6%); placebo: 1 of 9 (11.1%)

• Other AEs: inosine: 11 of 14 (78.6%); placebo: 7 of 9 (77.8%).⁵⁷

Masitinib (AB1010)

There are 2 registered clinical trials for this emerging drug. The first 1 is a phase II/III, multi-centre, randomized, double-blind, placebo-controlled, parallel-group, trial that assessed the efficacy and safety of masitinib in patients with ALS (NCT02588677; AB10015). Two different dosing regimens of masitinib were studied, 3 mg/kg/day and 4.5 mg/kg/day; all patients also received riluzole. The study was completed in March 2018.⁵⁸ Results and subgroup analyses related to study AB10015 were presented in 4 conference abstracts in 2017 and 2018,^40,42-44 in a publication in 2019,⁹ and in a recent published long-term survival analysis.²³

In the AB10015 study, eligible patients were adults aged 18 to 75 years with a diagnosis based on revised EI Escorial criteria of laboratory-supported probable, probable, or definite ALS, disease duration less than 36 months duration, and FVC of at least 60% at baseline.⁹ Patients were categorized according to the ALSFRS-R progression rate, calculated from disease onset to baseline with a dichotomizing cut-off at 1.1 points per month. Those with a post-onset ALSFRS-R progression rate of less than 1.1 points per month were categorized as normal progressors; they represent an estimated 84% of the ALS population. The other enrolled patients were fast progressors. It was predetermined that patents categorized as normal progressors receiving masitinib 4.5 mg/kg daily were predefined as the primary efficacy population. The primary end point was the decline from baseline of ALSFRS-R total score at week-48. Secondary end points included: time-to-event analysis (an end point driven by both death and a fixed disease progression on the ALSFRS-R score, defined here as a deterioration of 9 points from baseline or death), combined assessment of function and survival, change from baseline in the ALASQ-40 (ALS Assessment Questionnaire 40-item4) score (ALASQ-40 being an ALS quality of life patient questionnaire), FVC; limb muscle strength using hand-held dynamometry; and overall survival.⁹ Predefined secondary analyses included assessment of the broader normal and fast progressors masitinib 4.5 mg/kg daily cohort and low-dose (masitinib 3.0 mg/kg daily) cohorts. Safety monitoring was pursued until day 28 following discontinuation of the study drug. A total of 394 patients were randomized from 34 sites located in 9 countries: 133 patients received placebo, 131 patients received masitinib 3.0 mg/kg daily, and 130 patients received masitinib 4.5 mg/kg daily. The primary efficacy population (i.e., normal progressors receiving masitinib 4.5 mg/kg daily versus placebo) comprised 105 and 113 patients, respectively.⁹ For the primary efficacy population, the between-group difference in decline from baseline of ALSFRS-R total score at week-48 was 3.39 (masitinib = –9.24; placebo = −12.63); 95% confidence interval (CI), 0.65 to 6.13, P = 0.016. This represented a 27% slowing of ALSFRS-R deterioration. There were no differences in the decline from baseline of ALSFRS-R total score at week 48 for the secondary analysis populations of the normal and fast progressor masitinib 4.5 mg per kg daily cohort or the low-dose (masitinib 3.0 mg/kg daily) cohort.⁹ With respect to the impact of masitinib on the secondary end points for the primary efficacy population of normal progressors receiving masitinib 4.5 mg/kg daily, a difference in favour of masitinib was observed, compared to placebo, for 3 of these end points, with:

• a lower deterioration in quality of life, as measured by the ALSAQ-40 scale, with a between-group difference of 29% (change in least square mean from baseline of 19.42 for the masitinib versus 27.18 for the placebo group; P = 0.008)⁹

• a lower deterioration in respiratory function, as measured by FVC, with a between-group difference of 22% (change in least square mean from baseline of –26.45 for masitinib versus –33.99 for placebo; P = 0.03)⁹

• a delay of 25% in disease progression, as measured through the time-to-event analysis (20 months for masitinib versus 16 months for placebo, P = 0.016).⁹

There was no difference in overall survival in either the masitinib (4.5 mg/kg daily) or placebo groups. With respect to safety, the percentage of treatment-emergent AEs was 88% for masitinib 4.5 mg/kg daily, 85% for masitinib 3.0 mg/kg daily, and 79% for placebo. The percentage of serious AEs was 31%, 23%, and 18%, respectively. However, 1 isolated case (0.8%) of autoimmune-like hepatitis was reported in the masitinib 4.5 mg/kg daily group with the patient showing increased liver transaminase levels (grade 3) at week 24. This event resolved after masitinib was discontinued and a combination of prednisone and azathioprine was initiated. Three other cases of increased transaminases were reported (two patients on masitinib 4.5 mg/kg daily and 1 patient on masitinib 3 mg/kg daily). All were non-severe and resolved without sequelae following temporary treatment interruption.⁹ Compared to placebo, the addition of masitinib — administered orally at a dose of 4.5 mg/kg daily — to riluzole (100 mg daily) slowed the decline in the ALSFRS-R score of patients pertaining to the study’s predefined primary efficacy population.

The second study is a phase III, multi-centre, double-blind, randomized, placebo-controlled, parallel-group, trial of oral masitinib in the treatment of patients with ALS (NCT03127267; AB19001). Two ascending dose titrations of masitinib are evaluated in this study, 3.0 mg per kg daily with a dose escalation to 4.5 mg per kg daily after 4 weeks and 3.0 mg per kg daily with a dose escalation to 4.5 mg per kg daily after 4 weeks followed by another dose escalation to 6.0 mg/kg/day after 4 more weeks of treatment. All patients are also receiving riluzole 50 mg twice daily. This study is still recruiting patients and is targeted for completion in December 2022.²⁴ The objective of the AB19001 study is to confirm findings from study AB10015, while using a dosing regimen designed to optimize the benefit-risk balance of masitinib.⁴¹ The primary and secondary end points are the same as those of study AB19005.^24,41

Concurrent Developments

Several drugs are also in earlier clinical development for the treatment of patients of ALS. Although describing all potential drug candidates for the treatment of ALS is beyond the scope of this report, several other new or repurposed drugs were identified during this review. They are briefly described in Appendix 1 Tables 4, 5, and 6. Clinical trial information related to these drugs is summarized in Appendix 1 Tables 7, 8, and 9.

Considerations for Future Uptake

Given there are currently only 2 drugs approved in Canada for the treatment of patients with ALS, the number of emerging drugs in the research pipeline for this condition is encouraging. However, as many of these drugs still must complete their phase II and III clinical development, there is considerable uncertainty as to when they will become available to clinicians and patients. Nonetheless, it is possible to identify 2 key potential implementation considerations. The first 1 concerns the indication of certain drugs with respect to the subtype of ALS they will be intended for. Among the discussed drugs, prescribing antisense drug ION363 (jacifusen) would be expected to be limited to patients with fused in sarcoma (FUS)-ALS, a rare genetic form of ALS caused by mutations in the FUS gene. Also, prescribing masitinib may be limited to ALS patients categorized as normal progressors; that is, those with ALSFRS-R progression rate from disease onset to baseline of less than 1.1 points per month.⁹ This means that additional investigations may be required to characterize potential patient candidates for these drugs to ensure optimal patient selection for these therapies. In addition, should these drugs be eventually reimbursed by publicly funded drug plans, clear reimbursement criteria will need to be developed.

The second implementation consideration is the route of administration, and in some cases, the dosing schedule. Most considerations will not really be an issue for the several orally administered emerging drugs, although availability of a liquid form, in addition to the oral solid form, may be desirable for patients who develop swallowing difficulties. However, these considerations will be an issue for emerging drugs that require parenteral administration as additional support will be required. Drug administration issues may be more easily resolved for some parenteral drugs than others. For example it could be thought that a self-administration program could be developed by the manufacturer of zilucoplan as this drug requires subcutaneous administration.⁵⁹ Such program would also need to be adapted for caregivers of patients with more severe ALS as these patients may not be able to self-inject the medication. However, homecare services may be needed for patients to whom clinicians would prescribe drugs requiring IV administration; examples of such IV drugs include AT-1501,⁶⁰ fasudil,¹⁶ and SLS-005.⁶¹ This may also be the case for drugs with more complex dosing schemes such as engensis (VM202) which, based on current state of research, requires multiple intramuscular injections administered on bilateral upper and lower limbs on alternative weeks.⁵¹ Hospital services may also be required for 2 drugs that require intrathecal administration: tofersen⁶² and ION 363.⁶³ Of note, intrathecal administration involves the direct injection of the drug into the cerebrospinal fluid within the intrathecal space of the spinal column. It is a specialized way of administrating drugs that requires appropriately trained hospital personnel.⁶⁴ Consequently, it may be expected that specialized programs would need to be developed to support administration of these drugs.

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99.Azienda Ospedaliero-Universitaria di Modena. NCT03359538: Rapamycin treatment for ALS (RAP-ALS). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03359538. Accessed 2021 Dec 17.

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103.Denali Therapeutics Inc. NCT04268784: A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL343 in healthy volunteers. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://www.clinicaltrials.gov/ct2/show/NCT04268784. Accessed 2021 Dec 17.

104.Sanofi. NCT04982991: Single ascending dose study of SAR443820 in healthy adult Chinese and Japanese female and male participants. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04982991. Accessed 2021 Dec 17.

105.Helixmith Co Ltd. NCT02039401: Safety study of VM202 to treat amyotrophic lateral sclerosis. Clinicaltrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2019: https://clinicaltrials.gov/ct2/show/NCT02039401. Accessed 2021 Dec 17.

106.Helixmith Co Ltd. NCT04632225: Safety of engensis in participants with amyotrophic lateral sclerosis (REViVALS-1A). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04632225. Accessed 2021 Dec 17.

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108.Clene Nanomedicine. NCT03843710: 31P-MRS imaging to assess the effects of CNM-Au8 on impaired neuronal redox state in amyotrophic lateral sclerosis (REPAIR-ALS). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/NCT03843710?term=CNM-Au8&cond=Amyotrophic+Lateral+Sclerosis&draw=2&rank=1. Accessed 2021 Dec 17.

109.Clene Nanomedicine. NCT04098406: Therapeutic nanocatalysis to slow disease progression of amyotrophic lateral sclerosis (ALS) (RESCUE-ALS). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04098406. Accessed 2021 Dec 17.

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112.Cudkowicz ME. NCT04436510: HEALEY ALS Platform Trial - regimen B verdiperstat. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04436510. Accessed 2021 Dec 17.

113.Cudkowicz ME. NCT04414345: HEALEY ALS Platform Trial - Regimen C CNM-Au8. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT04414345. Accessed 2021 Dec 17.

114.Cudkowicz ME. NCT04615923: HEALEY ALS Platform Trial - regimen D pridopidine. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/NCT04615923. Accessed 2021 Dec 17.

115.Cudkowicz ME. NCT05136885: HEALEY ALS Platform Trial - regimen E SLS-005 - trehalose. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT05136885. Accessed 2021 Dec 17.

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118.Orphazyme. NCT03491462: Arimoclomol in amyotropic lateral sclerosis. ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2021: https://clinicaltrials.gov/ct2/show/NCT03491462. Accessed 2021 Dec 17.

119.Cytokinetics. Press release, Cytokinetics announces start of COURAGE-ALS, a phase 3 clinical trial of reldesetiv in patients with amyotrophic lateral sclerosis. 2021 Aug 2; https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-start-courage-als-phase-3-clinical-trial. Accessed 2021 Dec 17.

120.Cytokinetics. NCT03160898: A study to evaluate efficacy, safety and tolerability of CK-2127107 in patients with amyotrophic lateral sclerosis (ALS) (FORTITUDE-ALS). ClinicalTrials.gov. Bethesda (MD): U.S. National Library of Medicine; 2020: https://clinicaltrials.gov/ct2/show/study/NCT03160898. Accessed 2021 Dec 17.

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Appendix 1: Concurrent Developments

Note that this appendix has not been copy-edited.

There are several drugs currently approved in Canada for non-ALS indications and that are being investigated for the treatment of ALS (Table 4).

Table 4: Repurposed Drugs — Description of Drugs Marketed in Canada for non-ALS Indications Under Evaluation for ALS

ALS = amyotrophic lateral sclerosis; GSK = glycogen synthase kinase; HSP = heat shock protein; mTOR = the mammalian target of rapamycin; NAD = nicotinamide adenine dinucleotide; SOD1 = superoxide dismutase 1.

Table 5 describes select new molecular entities in early development phases I or II for the treatment of patients with ALS.

Table 5: Description of Emerging Drugs in Early Clinical Development

ALS = amyotrophic lateral sclerosis; CD40L = CD40 ligand; DLK = dual leucine zipper kinase; eIF2B = eukaryotic translation initiation factor 2B; FUS = Fused in Sarcoma HGF = hepatocyte growth factor; IM = intramuscular injection; IT = intrathecal injection; IV = intravenous injection; RIPK1 = receptor-interacting Ser/Thr protein kinase 1; S/C: subcutaneous injection.

There are also other drug candidates for ALS that have progressed to a relatively advanced clinical development stage. However, their future may be considered uncertain mainly because some studies have not met their key endpoints (Table 6).

Table 6: Description of Emerging Drugs in Late Clinical Development with Uncertain Future

ALS = amyotrophic lateral sclerosis; C5 = complement component 5; HSP = heat shock protein; SOD1 = superoxide dismutase 1; IT = intrathecal

Table 9: Research Status of Emerging Drugs in Late Clinical Development with Uncertain Future

ALS = amyotrophic lateral sclerosis; ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; CAFS = Combined Assessment of Function and Survival; fALS = familial ALS; HSP = heat shock protein; IDMC = Independent Data Monitoring Committee; MAD = multiple-ascending-dose; PAV = permanent assisted ventilation; PD = pharmacodynamics; PK = pharmacokinetics; SAD = single ascending dose; sALS = sporadic ALS; SVC = slow vital capacity.