VALOR Biogen’s Tofersen trial: a look at the open label extension data

The Motor Neurone Disease Association are pleased to discuss the additional results from the Biogen phase 3 clinical trial of Tofersen which were presented at the 20^th European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) meeting in Edinburgh, Scotland, on the 1-3^rd of June 2022.

Tofersen is a type of potential treatment known as an antisense oligonucleotides (ASO) that targets a specific genetic mutation thought to cause motor neurone disease (MND). Tofersen has been designed to work by stopping the production of abnormal SOD1 protein that is toxic to motor neurons.

A previous clinical trial called VALOR was performed in people with MND. The 28 week-long VALOR study trialled Tofersen in a total of 108 people with the SOD1 genetic mutation of MND. You can read more about this trial in our previous blog here.

In the trial participants either took the medicine or a placebo (dummy drug) for 6 months. In short, the trial did show some hints that Tofersen was having some effect in reducing the amount of SOD1 protein in people with MND and that a potential marker of disease known as Neurofilament light chain was reduced. However, the primary outcome measure of MND progression known as the ALS functional rating scale (ALSFRS-R) did not show a significant difference between those taking the medicine and those taking the placebo. As a result, the final conclusion of the trial after treatment with Tofersen for 6 months was that the treatment did not result in improvements in people living with MND.

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However, the trial did not stop there. As there had been several positive hints (such as the SOD1 protein and biomarker reduction) that Tofersen was having some effect, the trial participants were continued to be closely monitored to see if taking the treatment for a longer time led to more of an effect. In this part of the trial everyone took the drug, regardless of whether they were previously in the drug treatment or placebo group. This is known as the ‘open label extension’ phase and participants have so far been analysed for a total time of 52 weeks. This setup resulted in two groups: an ‘early start Tofersen’ group who received the drug throughout all of the study (for 52 weeks), and the ‘delayed start Tofersen’ group that first received placebo (for 28 weeks) but then went on to receive the drug (from 28 to 52 weeks).

The new data presented at ENCALS showed results leading to cautious optimism that the treatment may be effective if given for a longer time. The ‘take home’ highlights of the results are presented below:

SOD1 protein levels reduced

Tofersen treatment reduced the amount of SOD1 protein levels. This is good news as it suggests that the treatment is engaging with the biology it is meant to, by reducing the amount of toxic SOD1 protein, and may be working as expected. The graph below shows that for the ‘early treatment group’ (green line) SOD1 protein levels lowered from the beginning of the trial over time and stayed reduced over the 52 weeks. In participants that started on placebo (blue line) it was only when they began the active treatment with Tofersen at 28 weeks did they see a reduction in SOD1 levels (solid blue line). Once Tofersen was given to this group at week 28 the protein levels decreased to amounts that were similar to those in the ‘early treatment group’.

Neurofilament levels in the blood reduced

Neurofilament light chain is a potential marker of nerve damage and appears in the blood as nerve cells are broken down. In the graph below the neurofilament levels in the blood of participants treated with Tofersen from the beginning of the trial (green line) lowered over time, an effect that could be seen just weeks after starting treatment and was observed throughout the 52 weeks. This indicates a possible reduction in nerve damage and therefore disease progression. In participants who were in the ‘delayed start Tofersen’ group (blue line), neurofilament levels were increasing while they were still being treated with placebo (blue dotted line), which shows that the disease was still progressing, and nerve cells were being damaged. However, neurofilament levels started to reduce when the group began Tofersen treatment at week 28 (blue solid line).

The linking of the decrease in neurofilament levels to a reduction in disease progression was further supported by a handful of functional assessment such as respiratory function and muscle strength.

Survival

In addition, data was presented showing survival of the trial participants. In summary a person’s probability of survival was greater if they had received the treatment at the beginning. The graph below shows that more participants in the ‘early start Tofersen’ group (green) lived longer compared to those in the ‘delayed start Tofersen’ group (blue line). This survival analysis goes beyond the 52 weeks due to the nature of recruiting for clinical trials as some people will have been recruited earlier and been on the trial longer compared to others. The community would now like to find out if people in the trial who were given Tofersen lived longer than an equivalent group of people who have never received Tofersen. We will update any further information on this and anything else as it is released.

In summary Tofersen shows some promise for people with the particular SOD1 mutations that the treatment is designed to work with.

This new data gives us hope that effective therapies for MND are now a reality and that with more investment, more research and continued interest from pharmaceutical companies, additional therapies that will benefit all people with MND are closer than ever before. This is indeed the case as a number of genetic therapies are in development and in clinical trials. None of this progress is possible without the continued support of the MND community, the dedication and commitment of researchers and the generosity and altruism of people living with MND, their families and carers.

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The VALOR open label extension phase of the clinical trial is still ongoing, where participants are continuing to be given Tofersen. We hope the potentially positive outcomes from this trial continue and provide hope that other potential treatments will prove positive and encourage the development of more potential therapies that will be applicable to all forms of MND. The trial data here does suggest, as might be expected, that the earlier a potential therapy be given the more beneficial a treatment may be. This is the basis of another trial of Tofersen, called ATLAS.

ATLAS is a Phase 3 clinical trial of Tofersen which has already begun recruiting in the U.S., Japan and some of Europe. The trial is currently ‘in preparation’ in the UK and we will update the community once we have more information. This trial seeks to determine the value and optimal timing to begin treatment with Tofersen in those who have SOD1 mutations but who have not yet started to see symptoms and are considered pre-symptomatic. Further information about ATLAS can be found here.

If you have a question about these results you can check out some frequently asked questions on our website. You can also email research@mndassociation.org.