TRICALS consensus statement on Tofersen

OPINION:

The consensus view of TRICALS neurologists is that Tofersen shows clear benefit for people with ALS due to SOD1mutation, especially if given early in the disease course, and support should be given for licensing in this group of patients.

Background

Neurologists at the TRICALS Centres throughout Europe have discussed the potential of Tofersen as a new therapy for a subgroup of people with amyotrophic lateral sclerosis (ALS, motor neuron disease, MND) at the TRICALS meetings, 28 to 30 September 2022, and subsequently 19 to 20 January 2023 in Amsterdam, Netherlands.

On 22 September 2022, Biogen published the results of their Phase 3 trial of the antisense oligonucleotide, Tofersen, for SOD1 ALS. The drug is intrathecally administered by monthly lumbar puncture. While the trial did not meet its primary or secondary endpoints at 6 months, the TRICALS neurologists were of the view that the outcome of this trial requires a balanced and considered interpretation when considering how best to advise those with ALS and their families. The trial was extended for a further 6 months as an open label study, which remains ongoing. These results showed a therapeutic benefit of Tofersen when accounting for neurofilament light (NFL), a marker of prognosis. Furthermore, the study showed benefit in measures of survival, respiratory function, hand strength and biological markers of disease progression, slowing decline in across all domains.  For ALS patients with SOD1mutation, the evidence suggests Tofersen significantly slows disease progression if given early enough, but time is needed to see the clinical benefit, whereas the biological response occurs sooner.

What is Tofersen?

Tofersen is an antisense oligonucleotide designed to bind to SOD1 messenger RNA, marking it for destruction by cellular systems, thereby reducing the amount of toxic protein present. Patients receive the drug by lumbar puncture monthly.

What is known about the effectiveness of Tofersen?

International researchers from 10 countries working with Biogen ran a 24-week double-blind placebo-controlled trial of Tofersen, followed by 4 to 8 weeks observation. The trial included 108 participants, randomized 2:1 to active therapy or placebo. Treatment was given every two weeks for the first three doses, and then four-weekly for the next five doses. At the trial end, patients were offered the option to participate in an open-label extension for up to 236 weeks, while remaining unaware of their trial-group assignment. Results of the combined analysis at 52 weeks of the double-blind study and the extension study have been presented. These show that at the 28-week point, there was a drop in SOD1 protein levels in the spinal fluid in the active treatment group compared with the placebo arm, and a drop in the NFL levels in blood. There was no corresponding statistically significant difference between the two arms for survival, grip strength or function at 28 weeks, although the respiratory function as represented by slow vital capacity was different between the two groups. In the extension study, analysis at 52 weeks showed sustained reduction in the spinal fluid SOD1 levels and blood NFL for the treatment arm and a reduction to the same levels for those with a delayed start due to having been in the placebo arm. Clinical measures of function, strength and vital capacity showed increased separation between the two groups, becoming statistically significant for all measures by 52 weeks. Measures of survival were presented at 130 weeks, where there was a clear separation between the two groups.

The opinion of the TRICALS neurologists

While the results of the primary and secondary analysis technically show no benefit of Tofersen, this is likely because the clinical benefit lags behind the biological effect, and a 28-week trial is not sufficient to see a difference in the clinical endpoints used. This view is supported by the observation of target engagement in reduction of SOD1 seen by 12 weeks and sustained, biomarker response in reduction of plasma NFL seen by 12 weeks and sustained, but clinical effects on function, strength and respiration showing a trend at 28 weeks, but statistical separation by 52 weeks, and survival differences needing about 60 weeks to show separation.

The consensus view of TRICALS neurologists is that Tofersen shows clear benefit for people with ALS due to SOD1mutation, especially if given early in the disease course, and support should be given for licensing in this group of patients.

Signatories:

Ammar Al-Chalabi, King’s College London, UK

Adriano Chio, University of Turin, Italy

Philippe Corcia, Université de Tours, France

Orla Hardiman, Trinity College Dublin, Ireland

Caroline Ingre, Karolinska Institutet, Sweden

Christopher McDermott, University of Sheffield, UK

Monica Povedano, Hospital Universitari de Bellvitge, Spain

Philip Van Damme, UZ Leuven, Belgium

Leonard van den Berg, University Medical Center Utrecht, Netherlands

On behalf of TRICALS