Tofersen Falls Short in Phase 3 ALS Study, But Shows Favorable Trends

Treatment of ALS with tofersen resulted in differences in total cerebrospinal fluid SOD1 protein and neurofilament light chain, both markets of target engagement and neuronal degeneration.

Timothy Miller, MD, PhD

Timothy Miller, MD, PhD

Recently announced topline results from the pivotal phase 3 VALOR study (NCT02623699) and its open-label extension (OLE) of tofersen (Biogen) for the treatment of amyotrophic lateral sclerosis (ALS) showed that the investigational agent did not meet its primary end point in change from baseline in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Although, investigators observed favorable trends on multiple secondary and exploratory outcomes of biologic activity and clinical function.1

Using a joint-rank analysis, treatment with the antisense oligonucleotide did not reach statistical significance after 28 weeks of treatment on ALSFRS-R score (difference, 1.2 points; P = .97). Despite this, the agent appeared to help the trajectory of patients’ motor function, respiratory function, and quality of life. The company noted that it is still engaging with several leaders within the community to determine the potential next steps.

"The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients," principal investigator Timothy Miller, MD, PhD, director, ALS Center, Washington University School of Medicine, St Louis, said in a statement.1 "The wait for new options has been long and difficult for the ALS community, and we welcome this important research advancement in this difficult to treat disease space."

READ MORE: Positive Phase 1 Results, Regulatory Progress Announced for 2 Therapeutics in ALS

VALOR was a double-blind, placebo-controlled study that evaluated the effects of tofersen 100 mg in a cohort of 108 adults with ALS and a confirmed superoxide dismutase 1 (SOD1) mutation. Sixty of the participants met the study’s enrichment criteria for a rapid disease progression and thus comprised the primary analysis population or the "faster-progressing population." The other 48 participants did not meet these prognostic criteria and were thus categorized as the "slower-progressing population."

At the end of treatment phase, investigators observed differences of 38% and 26% in the faster- and slower-progressing populations, respectively, compared with placebo, in total change of cerebrospinal fluid (CSF) SOD1 protein, a secondary end point that indicates target engagement. The second key secondary end point, change from baseline in neurofilament light chain (NfL), resulted in differences of 67% in the faster-progressing population and 48% in the slower-progressing population with treatment of tofersen.

Procedural pain, headache, pain in extremity, fall, and back pain were the most observed adverse events (AEs) among patients who received treatment. Most of the AEs observed, both in VALOR and the OLE, were mild to moderate in severity. In total, 18.1% of tofersen-treated patients experienced serious AEs compared with 13.9% of those on placebo. Discontinuation of treatment due to AE was reported in 5.6% of those in the tofersen group, whereas no discontinuations occurred in the placebo group. Serious neurologic events were reported in 4.8% of patients receiving tofersen in VALOR and its OLE, including 2 cases of myelitis (2.0%). One death, deemed not related to study drug, was reported in the tofersen-treated group.

Those with faster-progressing ALS demonstrated favorable trends on measures of respiratory function (Slow Vital Capacity; difference, 7.9% predicted) and muscle strength (Hand-held dynamometer; difference, 0.02 points) following treatment with tofersen. Similar trends were observed across multiple exploratory patient-reported outcome measures of disease severity, quality of life, and fatigue.

"Data from the tofersen phase 3 study and its open-label extension showed signs of slowing disease progression in people with SOD1-ALS, a rare, devastating disease that leads to loss of everyday functions and ultimately death," Alfred Sandrock Jr, MD, PhD, head, Research and Development, Biogen, said in a statement.1 "Following discussions with investigators, bioethicists, and having listened to the voice of patient advocacy groups, we will broaden early access to tofersen to all eligible SOD1-ALS patients through our already established expanded access program. We are grateful for the courageous efforts of patients, families, advocates, and the scientific community who have contributed to this important research."

VALOR has multiple objectives and is built in a 3-part design. Part A was a single ascending dose component, while Part B was the multiple ascending dose component. Part C is the fixed-dose portion, making the overall phase of development as 1/2/3. The phase 1/2 results from VALOR were published in the New England Journal of Medicine in July 2020, suggesting that the agent reduces the concentration of SOD1 in the CSF of patients.2

Over a period of 12 weeks, the difference in the change from baseline in CSF SOD1 concentration favored that administered intrathecal tofersen, which was assessed in a number of doses—20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), and 100 mg (n = 10)—compared with placebo across doses (n = 12).

The geometric mean SOD1 concentration at baseline among those who received tofersen was 79.9 ng/mL in the 20-mg dose group, 140.9 ng/mL in the 40-mg dose group, 102.5 ng/mL in the 60-mg dose group, and 139.8 ng/mL in the 100-mg dose group. Comparatively, for placebo, the mean concentration was 84.6 ng/mL. At Day 85, the differences between the tofersen groups and placebo were 2 percentage points (95% CI, −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose. Respectively, the geometric mean ratios of the SOD1 protein concentrations among participants who received tofersen decreased overall by 1%, 27%, 21%, and 36%. Among those who received placebo, the ratio decreased by 3%.2

1. Biogen announces topline results from the tofersen phase 3 study and its open-label extension in SOD1-ALS. News release. Biogen. October 17, 2021. Accessed October 18, 2021.
2. Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1—2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020; 383:109-119. doi: 10.1056/NEJMoa2003715
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