Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a “real‐world” setting

Abstract

Objective

Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

Methods

This was a single‐center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes.

Results

Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: −57.9%; mean change CSF pNFH: −67.6%). There was apparent disease stabilization as assessed by the ALSFRS‐R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85).

Interpretation

This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.

Introduction

Mutations in SOD1, the gene encoding superoxide dismutase‐1 (SOD1), are present in 1–2% of all amyotrophic lateral sclerosis (ALS) patients and 20% of patients with “familial” ALS. ¹ Mutations in SOD1 result in disease via a toxic “gain of function” mechanism, whereby mutations promote aggregation of SOD1 protein. Tofersen is an antisense oligonucleotide that binds to and facilitates RNase‐mediated degradation of SOD1 messenger RNA, thereby reducing SOD1 protein production. ² Tofersen, designed for the treatment of people with ALS associated with mutations in SOD1 (referred to as SOD1 ALS in the remainder of this manuscript), is delivered via intrathecal administration. Results from the Phase 3 VALOR study and 6 months of its open‐label extension (OLE) showed meaningful differences in ALSFRS‐R, muscle strength, respiratory function, and quality of life. ³ Neurofilaments, nonspecific biomarkers of neurodegeneration, were substantially lowered by tofersen. Based on the reduction in neurofilament levels tofersen (Qalsody) was granted accelerated approval by the FDA in April 2023.

Our group participated in an investigator‐initiated investigational new drug (IND) application as part of the Biogen‐sponsored expanded access program (EAP) to treat patients with SOD1 ALS. The Washington University in St. Louis Institutional Review Board approved the IND. All participants provided written informed consent. Each participant had a confirmed, pathogenic, mutation in SOD1 and received 100 mg of tofersen via intrathecal administration. The dosing regimen included three loading doses at 14‐day intervals followed by monthly maintenance doses, the same regimen suggested in the current prescribing label for tofersen (Qalsody). Six patients transitioned from the EAP to our clinical dosing program, one patient transferred to another facility, and the most recent patient entered directly into our tofersen clinical dosing program. In this study, we report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures.

Methods

Study design

This was a retrospective, single‐center study of patients with SOD1 ALS receiving treatment with tofersen. Patients with SOD1 ALS (n = 7) were identified through their participation in the tofersen EAP and the tofersen clinical program at Washington University in Saint Louis from November 2021 to February 2024. The inclusion criteria were a confirmed diagnosis of ALS with an SOD1 mutation, age greater than 18 years, and currently on tofersen therapy. Demographic data, clinical characteristics, and SOD1 mutation documentation were collected. Phosphorylated neurofilament heavy chain (pNFH) in the CSF and serum neurofilament light chain (NfL) were measured by commercial assays (Eurimmun ELISA, Lübeck, Germany and ultrasensitive single‐molecule array (Simoa) assay, Quanterix Inc., Billerica, Massachusetts, USA, respectively). Data were collected between November 2021 and May 2024.

Study outcomes

Standard clinical assessments included assessment of function with the ALSFRS‐R (range, 0–48, with higher scores indicating better function), and strength measured using handheld dynamometry (HHD). The rate of progression of ALS was calculated as [(48 − ALSFRS‐R)/disease duration]. ⁴ , ⁵ We also calculated the expected ALSFRS‐R that we defined as the expected ALSFRS‐R if the patient had not received tofersen treatment (individual progression rate at start of tofersen treatment × months on treatment). Additional outcomes included functional independence measure motor score (FIM motor score; range, 13–91, with higher scores indicating better functional independence), and quality of life, as assessed with the ALS Assessment Questionnaire 5‐Item Form (ALSAQ‐5), a disease‐specific patient self‐reported health status questionnaire. ⁶ Four participants had longitudinal assessments with the 10‐meter walk test (10MWT), Timed Up and Go test (TUG), and 30‐s Sit to Stand Test performed by board‐certified physical therapists in outpatient physical therapy.

Standard protocol approvals, registrations, and patient consents

The study protocols were approved by the Washington University in St. Louis Institutional Review Board. Written informed consent was obtained from all patients that participated, registered at www.clinicaltrials.gov (NCT04972487, NCT05725759).

Statistical analysis

This is a descriptive study. Descriptive statistics were used (mean, median, ranges, frequencies, and percentages) and performed with GraphPad Prism version 10.0.2 (GraphPad, San Diego, California, USA).

Results

Study participants

Patient demographic, genetic, and clinic characteristics at baseline are summarized in Table 1. Overall, 7 patients with SOD1 ALS received treatment with tofersen in the clinical setting at our institution. The median age of patients at initial visit was 64 years (30–75 years), while the average disease duration from symptom onset to start of tofersen was 62.7 months (SD = 84.3). All patients had “slower” progressing ALS (defined by a delta ALSFRS‐R of <0.9/month). ⁴ , ⁵ At initiation of tofersen treatment, the mean ALSFRS‐R score was 35.1 (SD = 11.4) and the mean delta ALSFRS‐R score was 0.36 (SD = 0.26). The mean tofersen treatment duration was 18.4 months (range 7–30). There was sufficient data on 6 patients to calculate a treatment mean ALSFRS‐R score and treatment mean delta ALSFRS‐R, 36.5 (SD = 11.2) and 0.17 (SD = 0.09), respectively. The change in treatment delta ALSFRS‐R ranged from 0.02 to 0.51 indicating varied degrees of disease slowing in patients.

Table 1.

Clinical and genetic characteristics.

Patient	M/F	SOD1 mutation	Genotype	Family history	Disease duration (months) a	Baseline ALSFRS‐R a	Baseline ΔFS a	Tofersen treatment (months)	Treatment ΔFS b
1	F	p.A90V	Heterozygous	N	264	11	0.14	23	0.12
2	M	p.D91A	Heterozygous	Y	72	41	0.10	28	0.06
3	M	p.G73S	Heterozygous	N	12	38	0.83	17	0.32
4	M	p.V15L	Heterozygous	N	24	40	0.33	30	0.13
5	F	p.I114T	Heterozygous	N	24	38	0.42	19	0.26
6	M	p.A96V	Heterozygous	N	31	31	0.54	5	– c
7	M	p.I150T	Heterozygous	N	12	44	0.31	7	0.11

ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale Revised; CSF pNFH, CSF neurofilament heavy chain in CSF; ΔFS, delta FS, the slope of ALSFRS‐R over time (i.e., rate of disease progression); F, female; M, male; serum NfL, serum neurofilament light chain in serum; SOD1, superoxide dismutase‐1.

^a At initiation of tofersen treatment.

^b As of most recent tofersen treatment month.

^c Insufficient longitudinal data to calculate a treatment ΔFS.

Longitudinal changes in serum NfL and CSF pNFH

In all patients, both serum NfL and CSF pNFH were reduced during tofersen treatment compared to baseline (delta serum NfL: −57.9%, range −6 to −67; delta CSF pNFH: −67.6%, range −3286 to −349). Results are summarized in Table 2 and Figure 1.

Table 2.

Biochemical analysis data for serum and CSF from ALS patients.

Biochemical parameter	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7
Serum NfL (pg/mL)
Baseline	22	58	89	66	62	51	34
Change a	−27.27%	−62.1%	−75.28%	−81.82%	−38.71%	−41.18%	−79.41%
CSF pNFH (pg/mL)
Baseline	692	890	1168	3666	2637	3095	1331
Change a	−50.43%	−60.79%	−43.66%	−91.43%	−70.57%	−80.19%	−75.91%

CSF pNFH, CSF neurofilament heavy chain in CSF; serum NfL, serum neurofilament light chain in serum.

^a Change from initiation of tofersen treatment to the last measured value.

Figure 1.

Effect on serum NfL and CSF pNFH (N = 7). Longitudinal changes in neurofilament before and during treatment with tofersen. (A) Serum NfL; (B) CSF pNFH. CSF pNFH, CSF neurofilament heavy chain in CSF; serum NfL, serum neurofilament light chain in serum.

Clinical functional outcome measures

There was sufficient longitudinal data on 6 patients. All patients showed apparent stabilization or slight functional improvement as assessed by the ALSFRS‐R total score, mean change 1.1 (SD = 0.7) (Fig. 2A). More striking is the attenuation of ALS progression when compared to expected ALSFRS‐R scores based on ALS progression rate at start of tofersen treatment × months on treatment (Fig. 2A). Based on the most recent assessments, the mean ALSFRS‐R was 36.2 (SD = 11.5) compared to the mean expected ALSFRS‐R of 28.7 (SD = 10.7) if patients had gone without tofersen therapy, with an estimated 52% slowing of disease progression. Muscle strength was measured by HHD total score (total sum of deltoid flexion, elbow flexion, elbow extension, wrist extension, first dorsal interosseous, abductor pollicis brevis, hip flexion, knee flexion, knee extension, and dorsiflexion). HHD total score data was available for 6 patients. Muscle strength improved for 5 patients from baseline as measured by the HHD total score and mean change in muscle strength improved during tofersen treatment compared to baseline (delta HHD total score: 11.2%; range −13.4 to 46.1) (Fig. 2B). There was notable improvement in functional independence assessed by the FIM motor score. On average, participants gained 5.13 points (SD = 3.85) in functional independence (Fig. 2C). Patients 2, 3, 4, and 7 had longitudinal functional assessments performed independent of the study team by board‐certified physical therapists. These patients demonstrated improved mobility and gait performance assessed by 10MWT, TUG test, and 30‐s Sit to Stand (Fig. 2D–F).

Figure 2.

Clinical functional outcomes. Changes in ALSFRS‐R, HHD, FIM motor score, 10MWT, TUG, and 30‐s sit to stand. All panels reflect changes from initial assessment to the last measured value. (A) ALSFRS‐R Total Score; (B) FIM Motor Score; (C) Handheld Dynamometry Total Score; (D) 10MWT; (E) TUG; (F) 30‐s sit to stand. 10MWT, 10‐meter walk test; ALSFRS‐R, ALS Functional Rating Scale‐Revised; FIM, functional independence measure; HHD, handheld dynamometry; m/s, meters per second; TUG, timed up and go. Expected; expected ALSFRS‐R is progression rate at start of tofersen treatment × months on treatment. For figures (C) through (F) Patient 2 used front wheeled walker a rollator and left ankle foot orthosis, Patient 3 used a right ankle foot orthosis, Patient 4 used a rollator and bilateral ankle foot orthoses, and Patient 7 used a right ankle foot orthosis as needed for functional tasks.

Patient reported outcomes

There was sufficient data for 6 patients. The mean ALSAQ‐5 total score at baseline was 40 (SD = 17.0; scored 0–100, lower scores denoting better quality of life). ⁶ There was essentially no change in quality of life over time, 40.7 (SD = 20.2).

Safety and adverse events

Most adverse events related to tofersen treatment were mild to moderate in severity and consistent with ALS disease progression or known side effects of lumbar puncture. The most common adverse events included procedural pain, back pain, post‐dose myalgias, and headache. Approximately 42.86% of patients had elevated CSF protein concentrations at baseline. The mean CSF protein concentration increased by 118.96% (range −2.33% to 423.68%) with tofersen treatment. A lymphocytic predominant CSF pleocytosis was observed in all patients at different time points during the course of tofersen treatment with no specific clinical correlation. The underlying cause of the increased CSF protein and white cell counts, also observed in participants in Phase 1–3 trials of tofersen and their associated OLEs performed to date, remains unclear.

Three patients developed post‐dose myalgias within about 24–48 h of dosing at varying times in their treatment course, some more predictable and consistent than others. These consisted of muscle pain and soreness in hips, thighs, sacral regions, and/or distal legs with intermittent shooting pains. The symptoms were very consistent with what the authors have observed in a number of trial participants receiving tofersen. Symptoms resolved over the course of several days with acetaminophen or ibuprofen as needed. Use of periprocedural low‐dose corticosteroids, an intervention used by the authors with some tofersen trial participants was not required for any patient in this cohort. Beyond the post‐dose myalgias, adverse effects were minor and limited to mild peri‐procedural pain with near immediate resolution without intervention.

While there were no definite serious adverse events, 1 year into her clinical dosing, Patient 1 was found to have a precipitous decline in strength during a clinical encounter with her outpatient neuromuscular provider, relative to her most recent encounter. The patient had not recognized these changes but given the lack of a clear etiology for this exam change, and the known risk for serious adverse effects with tofersen, her provider referred her for a contrast enhanced MRI of the brain and spine, which showed diffuse enhancement of the conus medullaris and cauda equina nerve roots. The abnormalities on imaging coincided with the patient's highest recorded cell counts on CSF analysis. Additional CSF testing pursued at the first dosing visit after this MRI finding showed three oligoclonal bands unique to the CSF. A CSF IgM index, as performed by Reilich et al. was not performed. ⁷ The patient remained asymptomatic, and the motor deficits were no longer evident on subsequent evaluations by her regular neuromuscular provider. The patient opted to continue tofersen therapy, uninterrupted, and just entered her third year of tofersen therapy without any subsequent issues identified by the patient, the study team, or her neuromuscular provider. Patients 2 and 5 both had contrast enhanced MRI of the lumbosacral spine, which showed known lumbar spine degenerative disc disease, but no abnormalities to suggest that the post‐dose myalgias they experienced (mentioned above) were attributable to a polyradiculitis.

Discussion

About 2% of all cases of ALS and about 20% of familial ALS cases are attributable to pathogenic mutations in SOD1. ¹ , ² , ³ Tofersen is an ASO shown to reduce total SOD1 protein in the CSF, CSF and plasma neurofilaments, and slow the rate of decline in clinical function and strength. Our early clinical experience with this agent through the Biogen sponsored EAP program and now the tofersen clinical dosing program has yielded highly encouraging results consistent with the robust effects characterized by the VALOR + 6‐month OLE read out, and findings by Meyer et al. that showed similar decreases in NfL in response to tofersen in the clinical setting. ⁸ , ⁹ Fortunately, and most importantly, this biomarker effect has been paralleled with a stabilization of motor function, as measured by the ALSFRS‐R, HHD, and improvements measured on the FIM motor score. In addition, comparable findings of disease stabilization or slight improvement based on ALSFRS‐R and HHD, with reductions in CSF and serum NfL, were recently reported in a multicenter study of 17 patients with SOD1 ALS on long‐term tofersen treatment. ¹⁰

A similar, albeit less robust, reduction in CSF and serum neurofilaments in a D91A/D90A heterozygote patient was also encouraging, and in our opinion suggests that this particular mutation is likely pathogenic in the heterozygous state in some individuals, not only the homozygous state, a hypothesis further supported by the recent observation of a similar effect in this population by Weishaupt et al. ¹¹ Another possible conclusion from the D91A/D90A heterozygote is that lowering SOD1 protein is beneficial for all ALS regardless of SOD1 genotype, an interesting and provocative hypothesis with some literature support, but warranting further investigation. ¹² , ¹³

While our sample size is too small to draw conclusions about SOD1 mutations in apparently “sporadic” disease, it is noteworthy that most of the participants (85.7%) had no family history to suggest that they would harbor pathogenic SOD1 mutations. This finding emphasizes and strongly supports the concept that offering genetic testing and genetic counseling, for SOD1 mutations at a minimum, should now be standard of care for patients at the time of ALS diagnosis. ¹⁴ The VALOR study demonstrated a trend favoring early‐start tofersen compared to delayed initiation of tofersen. The ATLAS Study should provide important insights for pre‐symptomatic familial SOD1 variant carriers and the impact of early treatment with tofersen (ClinicalTrials.gov number, NCT0485698). ¹⁵

Of equal importance is the reassuring safety profile of tofersen in the clinic setting, which parallels the reassuring safety profile generated from the studies performed to date. ³ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ There were notable adverse events without any definite serious adverse events. Three patients developed post‐dose myalgias, with onset 24–48 h post dosing, and symptom severity lessened over time. Patient 1 had an abrupt transient decline in strength 1 year into her treatment. She was the most advanced of all patients in this cohort with 22 years of disease at start of tofersen treatment, baseline ALSFRS‐R score of 10/48, and is status post tracheostomy on mechanical ventilation. There was no clear etiology to her transient decline in strength on exam and we hypothesize that her transient decline in strength was perhaps magnified due to the patient's relatively low functional reserve. Overall, her strength declined 13.4% over the course of her tofersen therapy; however, she continues treatment without development of additional issues. Abnormalities in the CSF profile on routine analysis had no clinical correlations and is a known, common observation in participants receiving tofersen. The clinical significance, if any, of this finding remains unclear.

The ALSFRS‐R was stable or demonstrated a mild improvement over longitudinal assessments and there was no clinically meaningful decline for any individual paient. ¹⁶ Although there is caution in interpreting plateaus and mild improvements in ALSFRS‐R as an indication of treatment response and disease stabilization, we find it compelling that there was sustained improvement in several patients across multiple objective functional mobility outcome measures over multiple time points. ¹⁷ , ¹⁸ The duration of tofersen therapy for some of the individuals in our cohort (i.e., particularly our earliest EAP participants) represent the longest reported to date in the clinical setting, and provide evidence of a sustained benefit to tofersen extending into Year 3 on drug. Patients maintained high levels of quality of life, consistent with findings that “slower” disease progression is associated with higher levels of emotional well‐being in ALS. ¹⁹ Interestingly, the preservation of function and disease stabilization did not appear to influence quality of life as assessed by the ALSAQ‐5. A possible explanation is that quality of life in patients with ALS appears to depend on factors other than muscle strength and function. ²⁰ Further research in selecting appropriate quality of life measurements in the setting of ALS recovery is needed.

Although the ALSFRS‐R is a standard functional outcome measure used in ALS clinical trials, it may not be sensitive to detect meaningful clinical changes and improved function in people with ALS on disease stabilizing therapy, particularly those with forms of disease associated with “slower” disease progression. The FIM motor score used here captured improvements in function in a more sensitive manner. This is likely because the FIM motor score measures the level of disability and indicates how much assistance is required for the individual to carry out activities of daily living. The FIM motor score may provide a more comprehensive assessment for recovery of function and should be included as an outcome measure in future ALS clinic trials. There are no normative data in the ALS population for FIM motor score, 10MWT, TUG test, and 30‐s Sit to Stand. These outcome measures have not been specifically validated to assess for function in an ALS population; however, extrapolating from other neuromuscular and neurodegenerative disorders, where these are validated outcome measures, we view improvement on these assessments as likely supportive of true functional recovery. ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ Future research is needed to evaluate these functional outcome measures in the setting of functional recovery in patients on disease‐stabilizing ALS treatment and consideration is warranted to include these outcome measures in future ALS clinic trials.

The results of the present study must be interpreted with caution, given the small number of patients in our cohort, most with “slower” disease progression rates at start of tofersen, different durations of tofersen treatment, and variable disease stages. The expected ALSFRS‐R was provided as a potential means of predicting how a patient would have done without tofersen treatment and is not an accepted or validated measure at this time. We acknowledge that ALS disease progression is non‐linear and that using delta ALSFRS‐R to estimate disease progression is inexact. Despite the fact that the mutations studied here are not historically rapidly progressive, we do consider the functional improvements and overall stability of the treated participants to be unexpected and likely related to treatment. Furthermore, additional research is needed to evaluate treatment response based on genotype, and epigenetic variables, as this may inform future clinical experience and guide expectations with patients receiving tofersen.

Conclusion

In summary, our clinical experience shows robust, significant, and sustained reductions in serum and CSF neurofilaments in SOD1 ALS patients treated with tofersen. These results are highly encouraging and recapitulates the effects demonstrated in the recent VALOR +6‐month OLE study. More importantly, these findings were accompanied by an apparent slowing of motor decline and preservation of function, as measured by the ALSFRS‐R, and improvements in functional independence assessed with the FIM motor score. Our understanding of neurologic and functional recovery in SOD1 ALS on tofersen is just coming into existence and it is important to think how to best optimize ALS recovery and capture meaningful changes. Future research is warranted to evaluate the benefit of neuromuscular rehabilitation in the setting of ALS recovery.

Author Contributions

RCB, SES, and TMM contributed to conception and design of the study. AM, JO, JWM, KMG, RCB, and SES contributed to acquisition and analysis of data. RCB, SES, and TMM contributed to interpretation of the data and drafting the manuscript.

Funding Information

The authors received no financial support for the research, authorship, or publication of this article.

Conflict of Interest

TMM has licensing agreements with C2N and Ionis Pharmaceuticals, has served on an advisory board and receives material support from Biogen and Ionis Pharmaceuticals, served on advisory board for UCB Pharma, is a consultant for Cytokinetics, Disarm Therapeutics, and Bioio, and received an honorarium from Denali and Regeneron. RCB has served on advisory boards for MT Pharma and Biogen, has a consulting role with Biogen, has equity in Neuroquestions LLC, and receives a recurring annual gift from a patient's family for research on neuralgic amyotrophy. The remaining authors have no conflicts of interest to disclose.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.