Tofersen is an antisense oligonucleotide being evaluated for the potential treatment of superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1 ALS).
In October 2021, the Phase 3 Valor trial failed to meet its primary endpoint after six months, although trends of reduced disease progression across multiple secondary and exploratory endpoints encouraged an extension of the study.
Now, combined Valor and open-label-extension 12 month data has shown a slowed decline in clinical function, respiratory function, strength, and quality of life with earlier initiation of tofersen.
“The ALS community has been actively pursuing new medicines for decades. To have data like these published in NEJM gives us energy and hope. We are now seeing in the data what we suspected about tofersen for a long time – that it has the potential to make a clinical difference for people living with SOD1-ALS,” said Merit Cudkowicz, M.D., co-principal investigator of the Valor trial and co-founder of the Northeast ALS Consortium, Director of the Healey & AMG Center for ALS and Chair of Neurology at Massachusetts General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.
SOD1 gene mutations
After the launch of its Alzheimer’s drug Aduhelm (aducanumab), tofersen represents one of Biogen’s most advanced drugs in its pipeline. The US FDA recently accepted tofersen’s New Drug Application (NDA) for priority review, with an action date of January 23, 2023.
Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease that results in the loss of motor neurons in the brain and the spinal cord that are responsible for controlling voluntary muscle movement. People with ALS experience muscle weakness and atrophy, causing them to lose independence as they steadily lose the ability to move, speak, eat, and eventually breathe. Average life expectancy for people with ALS is three to five years from time of symptom onset.
Mutations in the SOD1 gene are responsible for around 2% of the estimated 168,000 people who have ALS globally, leading to the production of a toxic form of the SOD1 protein.
Known as gene silencing, tofersen binds and degrades SOD1 mRNA to reduce synthesis of SOD1 protein production.
The initial Phase 3 trial, Valor, was a six-month randomized, double-blind, placebo-controlled study to evaluate the effects of tofersen 100 mg in adults with ALS associated with a SOD1 mutation. In total, 108 participants took part, with 76 receiving 100mg of tofersen and the rest a placebo. Of these participants, 95 enrolled in the ongoing open-label-extension. At the time of the analysis all participants had an opportunity for at least 12 months of follow-up, with a median exposure to tofersen of approximately 20 months.
The combined Valor and open-label-extension 12 month data showed sustained reductions in SOD1 protein (a marker of target engagement) and neurofilament (a marker of neurodegeneration) and slowed decline in clinical function, respiratory function, strength, and quality of life with earlier initiation of tofersen.
However, the 12-month data also highlighted some adverse advents: serious neurologic events including myelitis, chemical or aseptic meningitis, radiculitis, increased intracranial pressure and papilledema, were reported in 6.7% of participants receiving tofersen in Valor and its open-label-extension.
Key takeaways
Biogen says the results offer ‘important learnings regarding the biology of SOD1-ALS and the design of ALS clinical trials.'
“I see three key take home points from these data. First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And third, there is a meaningful clinical benefit when looking at the later time points in the open label extension,” said Timothy Miller, M.D., Ph.D., principal investigator of Valor and ALS Center co-Director at Washington University School of Medicine, St. Louis.
While the treatment only offers hope to a small percentage of MND patients, it is hoped that other mutations could be targeted in a similar way.
Professor Dame Pamela Shaw, Professor of Neurology and Director of SITraN at the University of Sheffield said: “Patients with SOD1 mutations are relatively rare, but this trial is going to change the future of MND trials for patients. Not only can we look at other genes which also cause MND, but we now have a biomarker which we can measure to see if a treatment is working. This is going to make trials much more efficient. In future we may be able to tell in three to six months if an experimental therapy is having a positive effect.”
The study has been welcomed by the MND Association, which also highlights the potential of other similar approaches in tackling motor-neuron disease.
“These latest results provide mounting confidence that Tofersen is having both a biological and a beneficial effect in people living with SOD1 MND,” Dr Brian Dickie, Director of Research Development at the MND Association said.
“They also provide important ‘proof of concept’ that similar gene therapy-based approaches may be helpful for other forms of the disease.”
