ALS Therapy Research and Development: Insights from Merit Cudkowicz, MD, MSc

Physician-investigators at Massachusetts General Hospital are leading worldwide efforts to tailor the research and discovery of novel, effective therapies for patients with amyotrophic lateral sclerosis (ALS). Among neurodegenerative diseases, ALS is the most rapidly fatal, with treatment limited to symptom management and mortality from onset generally within three years.

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"Partnerships with researchers and philanthropic support both at home and abroad have facilitated the rapid discovery of effective treatment options for ALS patients," explains Merit Cudkowicz, MD, MSc, chair of the Department of Neurology and director of the Sean M. Healey & AMG Center for ALS. "Our ability to simultaneously perform multiple clinical trials worldwide has prolonged the lives of ALS patients and transformed the landscape of ALS research."

Optimizing and Accelerating Discovery

Dr. Cudkowicz was an original co-founder and co-director of the Northeast ALS (NEALS) Consortium, which began in 1995 as a collaboration between nine academic centers and has since grown to 140 research centers worldwide. Their goal was to drive ALS research toward clinical trials that would increase the spectrum of therapeutic options for patients.

Until relatively recently, translation of advances in the understanding of ALS pathophysiology was hindered by a lack of infrastructure and coordination necessary to support clinical trials. Additionally, disease heterogeneity within the patient population often precluded the identification of appropriate outcomes for trials of a given therapy.

Addressing these limitations in the discovery process requires the flexibility and funding to rapidly adapt the drugs being tested to patient responses. In 2018, the launch of the Sean M. Healey & AMG Center for ALS offered an opportunity to initiate the Platform Trial for ALS. Platform trials utilize a master protocol to simultaneously evaluate multiple treatments, including combinations of treatments, and perform comparisons of competing treatments across a patient cohort.

The outcomes support the efficiency of this approach:

• Decreases in the time for patients to obtain treatments by 50%
• Reductions in research costs by at least 30%
• Increases in patient receipt of therapeutic interventions by 67%

Dr. Cudkowicz attributes the speed with which the platform trial was established to the wealth of experience with clinical trials at NEALS, the infrastructure at Mass General, and the generosity of Sean Healey and AMG.

"Platform trials generally require years to design and obtain funding," she says. "We stood up the Platform Trial for ALS within one year of its initial design and obtained data on four drugs approximately two years later."

The rapid progress in these trials continues: Enrollment will begin in May 2023 for a trial of the seventh drug to be tested in five years. Although over 80 companies have applied to be part of the Healey ALS Platform Trial for ALS, Dr. Cudkowicz describes the search for new drugs as an ongoing process of outreach and evaluation.

"Although not all of the companies have drugs prepared for a Phase 2 trial, the opportunity to identify solid science at an early stage is invaluable."

Transforming Ideas Into Innovations

Approximately 10% of ALS-affected patients present a family history of the disease (fALS), with the remaining patients classified as having sporadic ALS (sALS). Although different, the genetic presentation in both patient subsets results in the degeneration and death of motor neurons. ALS research has demonstrated promising results in identifying and addressing the mechanistic origins of neuronal dysfunction and death.

Rescuing Neurons From Degeneration

Healthy cells, including neurons, require mitochondria for energy and a functional endoplasmic reticulum to direct proper protein folding, modification, and transport. Dysfunction in either or both initiates a stress response that can ultimately lead to cell death. In one case, identifying compounds capable of targeting and rescuing each respective function resulted in the founding of a company and its subsequent role in ALS research.

Preclinical evidence demonstrated the efficacy of combining both compounds to increase neuron survival. A randomized, double-blind, placebo-controlled trial (CENTAUR) designed and conducted through the NEALS Consortium revealed that the combination drug (AMX0035) significantly slowed ALS progression and increased survival by 6.5 months. Dr. Cudkowicz was also the senior author on papers reporting results from patients enrolled in the open-label extension (OLE) of the trial, which revealed increased survival up to 10.5 months and reduced risk of death and tracheostomy or permanent assisted ventilation.

The OLE data were key to Health Canada and Food and Drug Administration approvals of the drug (Albrioza in Canada and Relyvrio in the U.S.) for treating adult ALS patients in 2022. The ongoing phase 3 trial (PHOENIX) to obtain additional safety and efficacy data finished enrollment in February 2023. Dr. Cudkowicz describes this as an opportunity to treat a larger population of ALS patients over a longer period of time.

"The CENTAUR study included only patients with rapidly progressing ALS," she explains. "The expanded inclusion criteria and longer timeline required by the European Medicines Agency for the PHOENIX study offer an opportunity to confirm treatment efficacy in a much broader global population of ALS patients."

Targeting RNA to Address the Effects of ALS-related Mutations

Pathologies associated with genetic alterations present in both fALS and sALS patients involve consequences stemming from the transcription of mutated genes. Subsequent translation of mutated transcripts can produce proteins demonstrating either gain or loss of function, mislocalization within the cell or a combination of both.

Recent evidence has reinforced the effectiveness of antisense oligonucleotides (ASOs) as a viable treatment modality through their ability to address these effects at the translation stage. ASOs are short, synthetic ssRNAs designed to selectively bind a complementary sequence present in specific RNAs. Their clinical utility is highlighted by an ability to be administered intrathecally, which promotes access to targets associated with neurodegeneration in both the brain and spinal cord.

Since the discovery of SOD1 as the first ALS-associated gene, reported in Nature by Robert Brown, MD, PhD—formerly of Mass General—and his collaborators, significant effort has focused on the effects accompanying its mutations and the wide variability in their clinical presentation. Among those efforts was a Phase I/II conducted through the NEALS Consortium in 2016 that published its findings in The New England Journal of Medicine (NEJM), showing that the dosing strategy for an ASO targeting SOD1 mRNA (Tofersen) to reduce the synthesis of misfolded SOD1 variants implicated in ALS pathogenesis.

The subsequent phase III trial, results summarized in the NEJM, and its OLE study reported the following effects of intrathecal administration of Tofersen to SOD1 ALS patients:

• Lower levels of SOD1 protein
• Significantly lower levels of a biomarker of axonal damage (neurofilament light chain), suggesting a substantial slowing of neurodegeneration
• Stabilized or improved clinical presentations during the longer-term follow-up period

As a co-principal investigator on the trial, Dr. Cudkowicz explains that although the primary endpoints were not met according to the six-month timeline, the longer-term outcomes are very encouraging. In fact, they are still following patients that participated in the Phase I trial.

"Advances in ASO technology along with these findings reinforce my early belief in their potential as an effective gene therapy for ALS patients," she says. "Our data suggest that although this strategy may require longer timelines, the outcomes appear largely in favor of the patients."

The Right Place to Address the Most Difficult Problems

According to Dr. Cudkowicz, Mass General fosters a culture of collaboration that promotes a unique ecosystem.

"Our trials have been consistently supported by every discipline and area within Mass General. The ability to engage in the research and perform the number of trials we have requires levels of support and effort that may not have been possible elsewhere," she says.

Although a substantial focus is put on the researchers involved in these discoveries, too little is often afforded to the patients who make such clinical trials possible. The Mass General community makes significant efforts to prioritize and accommodate ALS patients and their families.

"We want every patient to have access to both excellent care and opportunities to benefit from the latest research," says Dr. Cudkowicz. These aspects of excellent care include home visits to accommodate patients and providing care to caregivers.

"We represent a beacon of hope for ALS patients that come here knowing they have access to the latest clinical trials," she adds. "We want to ensure they receive the best care possible during that process."

Learn more about the Sean M. Healey & AMG Center for ALS

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