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First Gene Therapy for ALS Approved: What Patients Should Know

May 16, 2023

The FDA has approved tofersen (Qalsody), the first drug developed for patients with a rare form of ALS caused by mutations in a gene called SOD1. ALS usually causes paralysis and death within a few years of diagnosis and is particularly aggressive in some patients with SOD1 mutations.  

In a phase 3 trial to test tofersen’s effectiveness, the drug did not significantly slow disease progression during the 28-week study period. However, the trial demonstrated that tofersen reduced levels of the toxic SOD1 protein and lowered levels of neurofilament light chain, a marker of neuronal injury.  

Based largely on these findings, tofersen was granted accelerated approval by the FDA. But to remain available, the FDA will require an additional study confirming clinical efficacy. 

headshot of dr. neil shneider in a white columbia medicine coat

Several patients have received tofersen at Columbia University’s Eleanor and Lou Gehrig ALS Center. We spoke with the center’s director, Neil Shneider, MD, PhD, about how patients have fared and where he thinks tofersen will have the biggest impact. 

The clinical trial did not show patients benefited from tofersen; do you think the drug actually works?  

In my experience treating ALS patients and my limited experience with the drug, I believe tofersen slows disease progression and the rate at which function and mobility is lost. That translates into an improved quality of life. People live more independently; in my opinion, they live better and longer on the drug. 

But not everybody is going to have the same outcome. People will respond differently to this drug, depending on the specific mutation and nature of their disease. 

There is a great deal of variability in the disease among SOD1 ALS patients with different mutations. Perhaps the people helped most by tofersen are those with mutations associated with very aggressive disease, based on a comparison of their disease course with that of family members and others with the same mutation. 

I think we need to get this new drug to ALS patients and families and continue to work to provide whatever additional evidence is needed to obtain full approval for tofersen. 

We now understand that the benefits of tofersen take more than six months to become apparent. And I’m confident that a trial designed based on the knowledge we now have about tofersen and the timing of its effects would demonstrate its efficacy. 

What should families with a history of SOD1 ALS know about tofersen? 

The original clinical trial of tofersen only enrolled individuals who had symptoms of SOD1 ALS. 

But we think that the drug may be most effective in people who have SOD1 mutations but do not show any signs of the disease. A new trial (called ATLAS) is now enrolling these pre-symptomatic carriers of SOD1 ALS mutations, and I encourage anyone who has lost a family member to this disease to get genetic testing and counseling and see if they’re a candidate. 

Currently, tofersen is only available to pre-symptomatic individuals with SOD1 mutations through this clinical trial. 

If tofersen is successful in this trial, this data would most likely convince the FDA to keep tofersen on the market. 

Can tofersen work for other ALS patients?  

Some have suggested this may be possible, but I know of no convincing evidence that this drug—which specifically targets the SOD1 gene—would be useful in ALS patients who do not have a disease-causing SOD1 mutation. 

What tofersen’s approval does mean for other ALS patients is that different ALS drugs will probably be coming soon.  

The FDA’s tofersen decision was based in large part on the way the drug reduced a biomarker of neuronal damage. When levels of a protein called neurofilament light chain are high, we believe neurons are being damaged by the disease. If we know that reductions in neurofilament light chain mean the drug is working, future clinical trials can proceed much faster. We won’t have to wait months and months to see changes in symptoms in trial participants. And effective drugs can get to patients more quickly. 

This has important implications for our own program here at Columbia to develop therapeutics targeting mutations in the FUS gene, which cause another form of ALS.  

So even though tofersen’s use may be limited to a small percentage of people with ALS (SOD1 ALS affects a few hundred people each year), it’s exciting because it opens up a new avenue for the development of other ALS drugs.