The Broader Significance of a New Drug for a Rare Form of ALS

— The tofersen trial offers hope and lessons for the fight against ALS

by Jonathan D. Glass, MD May 15, 2023

A major milestone in the treatment of amyotrophic lateral sclerosis (ALS) occurred on April 25, 2023, when the FDA approved tofersen (Qalsody) for patients carrying the disease-causing mutation superoxide dismutase 1 (SOD1).

The story of the path to approval is informative of how an idea that began in academic laboratories in San Diego and St. Louis can be brought to fruition by true collaboration between academia and industry. Those continued relationships led to a clinical trial that turned out to be instructive for the clinical trial community on the importance of disease biomarkers and time in assessing the effectiveness of a drug for ALS.

Approximately 10% of ALS occurs in families (“familial” or fALS). Mutations in SOD1 account for about 20% of fALS, and thus only about 2% of ALS as a whole. This recent demonstration of a therapeutic intervention that can possibly stop, and potentially partially reverse, the relentless progression of disease suggests that, in this small population of ALS patients, ALS is a treatable disease. This is a small but important step toward the goal of making all ALS as a whole a truly treatable disease.

In 1993, it was first reportedby Teepu Siddique, MD, Robert H. Brown, MD, DPhil, and colleagues, that a mutation in the gene for SOD1 is a cause for fALS. Several decades of research have generated experimental data supporting various potential models for how SOD1 causes ALS. However, it was the demonstration of the therapeutic effect of knocking down the expression of the SOD1 protein using anti-sense oligonucleotides (ASO) that initiated the translational partnerships that led to the drug tofersen.

A first-in-human trial of an ASO against SOD1 administered directly into spinal fluid was published in 2013and a SOD1 ASO redeveloped for improved potency (tofersen) was brought to trial in 2016. The initial results in the tofersen phase I/II trial were encouraging, demonstrating reduction of SOD1 protein in response to the ASO. The phase III trial was disappointingly considered “negative” as it did not meet its primary endpoint of slowing disease progression as measured by the patient reported outcome measure, the ALS functional rating scale.

There were, however, interesting data from the phase I/II and phase III trials that led investigators and the FDA to look closer. Four patients in the first trial on the highest dose of tofersen showed slowing of disease, as assessed by a combination of the functional rating scale and measures of breathing and strength, which correlated with a reduction of SOD1 protein in the spinal fluid. In addition, levels of the exploratory neurofilament biomarker, which is a measure of disease activity in a number of neurological disorders, also declined in those treated with tofersen.

Though the phase III trial did not meet its specified primary endpoint at the end of the 28-week placebo-controlled phase, data from the open label extension was remarkably consistent with a true therapeutic effect. Patients originally assigned to the active tofersen arm continued to do well, and those moving from placebo to open label tofersen showed reduction of neurofilament and slowing of disease. Thus, following patients out to 1 full year allowed the therapeutic effect to reach a level that was significant and supported by concordant data from multiple clinical and biomarker measures.

The success of the tofersen trial teaches us a few things about ALS and ALS trials. First and foremost, the study suggests ALS is a treatable disease, and therapeutic intervention has the potential to provide clinically meaningful therapeutic effects. The approval of tofersen is a new beginning, targeting a small segment of the ALS population.

But I expect this success will soon be extended to other disease-causing genetic mutations and eventually to sporadic disease. This trial also provides important data that support neurofilament as a biomarker that correlates with clinical measures of disease progression, and indicate that a measurable therapeutic effect in ALS may take longer than just 28 weeks. And importantly, positive results come from close collaboration and partnership between academic researchers and industry.

Jonathan D. Glass, MD, is director of the Emory ALS Center.