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Msg  62347 of 62411  at  3/6/2023 3:49:22 PM  by


In support of Tofersen

I am a practicing neurologist that specializes in ALS. I have been treating patients with ALS for over 15 years. Historically I have not agreed with the approval of any medication without a positive phase 3 trials. I currently take care of a patient that is receiving tofersen at another city. This patient’s form of SOD1 is one of the more rapid ALS forms. Historically these patients do not live 1 year from onset of symptoms. This patient had a vary rapid course. Went from walking to a wheelchair in less than 3 months. We got this patient into the clinical trial extremely quickly. It has been over 3 years and the patient is still living and actually gained strength back! I cried after seeing this patient recently. With 15 years of doing ALS clinical trials, I have never seen a drug that truly convinced me there may be a cure until that day. I strongly believe his success was due to the timely manner of getting into the study. Although expanded access programs can provide access for some patients, not all providers have resources to provide EAPs and they take time to complete the required paperwork. These patients do not have this time. I recommend voting for the FDA accelerated approval of tofersen.

Cynthia L Bodkin, MD
Assistant Professor of Clinical Neurology


As an ALS neurologist and trialist, i am writing in support of approval for tofersen for people with SOD1 ALS. I have been involved in the trials for this treatment since the start and several people i care for with sod1 ALS are part of this study. In my 30 years as an ALS physician, this is the first study where i have personally seen people stop progressing AND.. some of them recover function. The dramatic effect also on NFL is a huge step forward for the field. There are now other treatments in development that lower NFL. Tofersen is a targeted treatment that works. Please vote in support of approval.


I am Professor of Neurology and Director of the Multidisciplinary ALS clinic at Mayo Clinic. I was a co-investigator on the VALOR trial and have patients currently enrolled in the Expanded Access Program for Tofersen. I am not being compensated by Biogen for my testimony.

In my review of the VALOR Phase 3 manuscript data (NEJM), subsequent analyses in Open Label Extension (OLE) that have been presented at ALS meetings, and my anecdotal experience with Tofersen in patients that we have treated, this is the first medication for ALS that appears to have clear, tangible benefits. As the data unfolds from VALOR (and importantly the OLE), it is clear that there were methodological flaws with VALOR (which were difficult to predict). Given what appears to be a robust clinical (and neurofilament) response with Tofersen, post-approval studies should continue. In my opinion, however, Tofersen should be approved for those with SOD1-ALS without delay.


I am writing to support approval of Tofersen treatment. The reason is I began phase 3 in 2019 and then switched over to the Open Label Extension. I was diagnosed in 2018 with SOD1 and was quickly enrolled into the trial. I have remained constant with from breathing, muscle strength where applicable, and ALSFR scale. I will be receiving my 53 injection this coming Monday and without this I feel I would not be here to write this. The reason I feel this is another family member with identical gene was diagnosed in 2019 and passed on 11 months later as he was unable at that time to receive the Tofersen; if he was able to access the drug I feel he would still be with us today. I believe the Tofersen is the only reason I am able to write this today and watch my children grow. Along with myself it gives hope to my children if they inherit the gene. This treatment is very important to the ALS community as it should lead to more treatments for other genes and sporadic ALS. Thank you for your time and please help the ALS community.


TRICALS consensus statement on Tofersen
4 March 2023
The consensus view of TRICALS neurologists is that Tofersen shows clear benefit for people with ALS due to SOD1 mutation, especially if given early in the disease course, and support should be given for licensing in this group of patients.
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 SOD1 mutation, 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 SOD1 mutation, especially if given early in the disease course, and support should be given for licensing in this group of patients.
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

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