Balancing hope and hesitation: A closer look at Tofersen approval for ALS

doctor injecting a patient

Accelerated approval of treatments may mean that ineffective medication is licensed. This may be the case for Tofersen, a new medication approved to treat ALS. Photo credit: Mat Napo via Unsplash


On the 25th April 2023, the FDA made the controversial decision to approve Tofersen, a drug manufactured by Biogen, as a treatment for a rare genetic variant of ALS. This variant only affects 2% of the estimated 168,000 people living with ALS globally. The decision has been met with significant scepticism after phase III clinical trials failed to show statistically significant improvements in disease progression.

…the FDA made the controversial decision to approve Tofersen…

ALS is a fatal neurological disease characterised by the degeneration of motor neurons. The disease manifests as muscle weakness, progressing to issues with breathing and swallowing, and eventually leading to paralysis and death. ALS is a devastating diagnosis without a current cure or proven treatment, and countless resources are being funnelled into finding a way to slow its progression.

Tofersen is specifically approved to treat patients with ALS associated with a mutation in the SOD1 gene. In a healthy cell SOD1 performs a vital protective role in neutralising reactive oxygen species. Reactive oxygen species are produced during many cell processes but can cause cell damage if their levels get too high. Patients with SOD1 mutations manufacture inappropriately high levels of SOD1 protein. These proteins build up within the cell and form clumps in the brain and spinal cord, which are not only toxic but also prevent SOD1 from carrying out its regular protective function. This leads to degeneration and death of motor neurons, resulting in the patient losing the ability to control their muscles.

Tofersen is a type of antisense oligonucleotide drug. These drugs target specific genes within a cell and can be very effective in diseases with a known genetic component. The drug binds to the molecule within the cell that is responsible for manufacturing the SOD1 protein, inhibiting its production. Scientists hope that Tofersen will slow the progression of ALS and offer patients a higher quality of life with more mobility and independence.

…the improvement in disease progression with the drug was not significantly different from disease progression with a placebo.

Tofersen recently completed phase III clinical trials, which evaluated the safety and effectiveness of the drug in 108 patients with SOD1-ALS. Disease progression was measured using the ALS Functional Rating Scale which is a disease severity score that takes into account motor impairment and respiratory symptoms. While patients who received the drug did have lower SOD1 protein levels, the phase III trial did not slow the rate of disease progression at a statistically significant level. This means that the improvement in disease progression with the drug was not significantly different from disease progression with a placebo. The scientific community thought that this disappointing result would spell the end of Tofersen’s journey through drug development.

However, the trial yielded interesting biomarker results. Tofersen decreased the levels of a molecule called neurofilament light chain (NfL), which may be a reflection of disease progression. NfL is released when neurons are damaged, therefore a high level of NfL protein can indicate a high level of neuron degeneration. Tofersen decreased NfL levels, perhaps suggesting that it was having a positive impact on brain health and slowing the death of neurons. It was therefore based on its ability to lower NfL levels that the FDA decided to approve this drug under its accelerated approval pathway.

The accelerated approval pathway allows drugs into the market that have potential for clinical benefit, but whose efficacy is yet to be proven. This program was first introduced to expedite the approval of HIV treatments in response to the AIDS epidemic. Following accelerated approval, the manufacturers must undertake phase IV confirmatory trials that verify the drug’s benefit. Should the drug prove to be ineffective in this additional testing, it will be removed from the market. However, a recent review of drugs on the accelerated approval pathway, by the British Journal of Medicine, revealed that half of the drugs have not been confirmed as clinically effective despite 20% of them having been on the market for more than 5 years. Seemingly, the process of undertaking phase IV confirmatory trials is not regulated enough, leaving room for companies to take advantage of this pathway.  

In principle, the accelerated approval system used to approve Tofersen should be revolutionary for rare diseases like SOD-ALS, where accessing enough patients to perform large clinical trials is challenging. However, this pathway has recently been criticised for approving drugs with little clinical evidence. The integrity and rigour of the approval process have been called into question, particularly in the case of aducanumab, a drug recently approved for the treatment of Alzheimer’s disease. This drug not only had little evidence of clinical benefit but was also associated with harmful side effects. A cost analysis of aducanumab indicated that this drug would likely have minimal improvements in disease outcome at an exorbitant cost to the patient, shedding doubt on the motives of the FDA in approving such drugs. Similarly, Tofersen comes with significant price tag at $185,000 per year of treatment raising questions of the cost-benefit of this drug too.

While the clinical data has yet to definitively prove that Tofersen improves patient outcomes, an open-label extension of the phase III trial (where a trial is continued for months to assess the long-term efficacy of the drug) has shown some promise. Improvement in motor function, respiratory function, and quality of life were reported, particularly if the treatment was initiated early in disease progression. Perhaps initial trials were too short to capture the potential of Tofersen for improving the lives of patients with ALS.

Drug approval decisions must be rooted in clear, convincing evidence. But for a disease with such fatal progression, any chance of improvement in quality of life for patients with ALS is so valuable. Tofersen’s effect on NfL and the recent open-label extension give us tentative hope that real clinical benefit could come from its approval despite the mixed success of the phase III trial.