Recent Advances in Amyotrophic Lateral Sclerosis (ALS) Research and Therapeutic Pipeline: Highlights from AAN 2024

Study 1: Real-world Evidence of Treatment Retention, Safety, and Tolerability of Edaravone in Canadian Patients with Amyotrophic Lateral Sclerosis

Purpose:To determine the real-world treatment retention, safety, and tolerability of edaravone in patients with amyotrophic lateral sclerosis (ALS) enrolled in the MTP-Patient Support (MTP-PS) program.

Background:Intravenous (IV) edaravone was approved by Health Canada in October 2018 for the treatment of ALS and has been shown in clinical trials to slow the rate of functional loss associated with ALS. In Canada, the MTP-PS program provides patient support services and is collecting real-world data from ALS patients receiving edaravone treatment.

Design/Method:This ongoing, observational, real-world study is collecting de-identified data from patients treated with edaravone who have participated in the MTP-PS program for up to 4 years with four pre-planned analyses. The Full Analysis Set (FAS) includes both edaravone-naïve and edaravone-experienced patients. Baseline demographics were assessed at the initiation of edaravone treatment.

Results:This analysis included 616 patients with Fas, of whom 73% had never used Edaravone. Patients who did not use Edaravone were predominantly over 55 years old (78%) and male (62%). The majority of patients had limb-onset Amyotrophic Lateral Sclerosis (ALS) (67%) and definite or probable ALS (65%). Most patients (78%) initiated intravenous Edaravone treatment within six months of ALS diagnosis and had previously received Luzole treatment (60%). Thirty percent of patients received intravenous Edaravone in an infusion clinic. The mean total ALS Functional Rating Scale score for NAS patients was 42.1, and the mean Forced Vital Capacity score was 95.8%. Patient retention rates for Edaravone treatment at 12 months and 24 months were 56.2% and 27.0%, respectively.

Conclusion:This study provides an in-depth understanding of the real-world demographic data and characteristics of patients treated with edaravone in Canada. The next step will be to evaluate treatment retention, safety, and tolerability in patients receiving edaravone. The resulting real-world evidence may be valuable for informing clinicians and payers, as well as enhancing patient support services.

Study Two: QRL-201-01 – A Multicenter, Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety and Tolerability of QRL-201 in Amyotrophic Lateral Sclerosis

Purpose:Evaluate the safety and tolerability of QRL-201 in patients with amyotrophic lateral sclerosis.

Background:>90% of patients with Amyotrophic Lateral Sclerosis (ALS) are characterized by the presence of cytoplasmic TAR DNA-binding protein 43 (TDP-43) aggregates and the loss of nuclear expression. The loss of nuclear TDP-43 leads to stathmin-2 (STMN2) mis-splicing, resulting in reduced expression in most ALS patients. STMN2 is crucial for nerve repair, axonal stability, and neuromuscular junction innervation. Our therapeutic approach is to correct STMN2 mis-splicing, thereby restoring protein function. QurAlis has demonstrated that this can be achieved using splice-switching antisense oligonucleotides (ASOs) in non-clinical studies. QRL-201, an investigational ASO, rescues STMN2 expression and protein function in disease models of neurons derived from patients at QurAlis Corporation, even in the continued presence of TDP-43 pathology.

Design/Method:QRL-201-01 is a double-blind, multiple ascending dose study in which approximately 64 ALS patients will receive QRL-201 or a matching placebo in a 6:2 ratio. The study design includes six dose-escalation cohorts and two exploratory cohorts. This study involves the collection of extensive biomarker data, utilizes sentinel participant dosing, and includes multiple safety reviews.

Results:The primary endpoint is the incidence of adverse events. The secondary endpoint will be the measurement of multi-dose pharmacokinetics (PK). The study will include multiple exploratory endpoints: 1) biomarkers of neuronal loss and STMN2 biology; 2) clinical outcome measures (ALSFRS-R, ROADS, SVC, HHD, electrophysiological tests); 3) CSF PK profile.

Conclusion:Quralis' mission is to bring breakthrough precision medicine technology to ALS patients. QRL-201-01 aims to evaluate the safety and tolerability of multiple doses of QRL-201 in ALS patients and explore the hypothesis that restoring STMN2 is a suitable disease-modifying approach in ALS.

Study Three: Results of the Healey ALS Platform Phase 2 Clinical Trial for Pridopidine in the Treatment of ALS

Purpose:Pudopidine was evaluated in the Phase 2 Healey ALS Platform trial.

Background:Pridopidine is an orally administered small molecule and potent Sigma-1 receptor agonist.

Design/Method:Eligible participants had El Escorial possible, probable, or definite ALS, symptom onset <36 months, and vital capacity >50% predicted. Pridopidine 45mg bid was compared with a shared placebo. The primary endpoint was the change in ALSFRS-R total score from baseline to 24 weeks. Secondary and exploratory endpoints included measures of speech, respiratory function, and quality of life. Pre-specified and post-hoc subgroups included definite + probable ALS, early onset (symptom onset <18 months), and rapid progressors (slope <-1 before baseline). Nominal p-values are reported.

Results:Pridopidine was well-tolerated, consistent with previous safety data. FAS did not meet the primary endpoint. Significant speech improvement was observed in the FAS group, and post-hoc analysis of early and rapidly progressing patients showed greater improvements in speech rate and clarity.

In confirmed ALS and early participants, Pridopidine showed favorable trends in ALSFRS-R progression and respiratory domains, with improvements observed in dyspnea. Greater ALSFRS-R improvements were seen in confirmed + possible ALS, early, and rapidly progressing participants. In confirmed ALS and early participants, there was a smaller decline in the ALSAQ-40 quality of life scale, eating, and communication. Kaplan-Meier survival analysis showed that the median survival time for confirmed + possible ALS and early participants extended from approximately 300 days to 600 days compared to delayed-start placebo participants.

Conclusion:Beneficial effects of Pridopidine were observed in speech (Fas) and multiple disease progression indicators. This includes increased survival time for confirmed + possible ALS and early participants. These observations inform the ongoing Phase 3 study program.

Study Four: Evaluation of the Safety, Tolerability, and Pharmacokinetics of QRL-101 in Two Phase 1 Studies: QRL-101-01 in Healthy Adults and QRL-101-02 in Adult ALS Patients

Purpose:Evaluate the safety, tolerability, and pharmacokinetics of QRL101 in healthy volunteers and ALS patients.

Background:Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that results in the loss of motor neurons in the motor cortex, brainstem, and spinal cord. In ALS, evidence of increased cellular excitability in peripheral nerves and central motor neurons has been observed through advanced neurophysiological, imaging, pathological, and biochemical techniques. Clinically, hyperexcitability is associated with reduced survival in ALS patients. QRL-101 is an investigational product targeting motor neuron hyperexcitability. Preclinical studies conducted in ALS models have shown that QRL-101 is an effective and selective positive allosteric modulator of KCNQ2/3 channels, capable of effectively reducing motor system hyperexcitability in ALS patients.

Design/Method:QRL-101 will be evaluated in two consecutive, randomized, placebo-controlled, double-blind Phase 1 studies. QRL-101-01 is an ongoing first-in-human single ascending dose (SAD) study involving approximately 40 healthy participants. The study design includes five dose-escalation cohorts, each with 8 participants, and the randomization ratio of the investigational drug to placebo is 6:2. Information from QRL-101-01 will be used to determine the safe and tolerable dose range for the subsequent multi-center multiple ascending dose (MAD) study (QRL-101-02), which will evaluate QRL-101 in approximately 24 adult ALS patients. Both studies will employ a sentinel dosing strategy and include multiple safety reviews.

Results:In these two studies, the primary and secondary endpoints will be the incidence of adverse events and the PK measurements of QRL-101. In QRL-101-02, additional exploratory endpoints will be evaluated to assess the impact of QRL-101 on clinical outcomes, as well as electrophysiological markers of motor neuron excitability in ALS patients.

Conclusion:These research findings will be used to advance the development of QRL-101 and other next-generation precision medicines for patients with ALS and other neurodegenerative diseases.