Hope for patients with amyotrophic lateral sclerosis

• The U.S. Food and Drug Administration (FDA) has fast-tracked registration of the drug tofersen based on the reduction of neurofilaments, a marker of neurodegeneration
• Amyotrophic lateral sclerosis associated with a mutation in the gene encoding the enzyme superoxide dismutase 1 (SOD1) is a devastating, fatal-causing ultra-rare genetic form of ALS3-4, with which there are approximately 330 people living in the U.S.

Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease that causes the loss of motor neurons in the brain and spinal cord that are responsible for controlling voluntary muscle movements. People with ALS experience muscle weakness and atrophy, resulting in a loss of independence through a gradual loss of the ability to move, speak, eat and eventually breathe. The average life expectancy for people with ALS is three to five years from the onset of symptoms.

Many genes are associated with ALS. Genetic testing helps determine if a person's ALS is associated with a genetic mutation, even if there are no known cases of the disease in their family. A mutation in the SOD 1 gene is diagnosed in about 2 percent of all ALS cases. There are about 330 people living with the disease in the United States. More than 15 percent of people with ALS are thought to have the genetic form of the disease, even though there may have been no known cases of the disease in their families.

The U.S. Food and Drug Administration (FDA) has registered tofersen at a dose of 100 mg/15 ml administered intrathecally for the treatment of adults with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1(SOD1) gene. This indication was approved in a fast-track registration procedure based on the reduction in plasma levels of neurofilament light chains observed in patients treated with tofersen. Neurofilaments are proteins that are released from neurons when they are damaged, making them a marker of neurodegeneration.

Continued registration in this indication may be contingent on verification of benefit in an ongoing confirmatory study, the Phase 3 ATLAS trial of tofersen for use in subjects with presymptomatic SOD1-ALS.

Tofersen is the first approved therapy targeting the genetic cause of ALS. Biogen has collaborated with Ionis Pharmaceuticals on the early development of the drug.

The efficacy of tofersen was evaluated in a 28-week, randomized, double-blind, placebo-controlled clinical trial in patients aged 23 to 78 years with ALS-induced weakness and an SOD1 gene mutation confirmed by a central laboratory. One hundred and eight (108) patients were randomized in a 2:1 ratio to treatment with tofersen 100 mg (n=72) or placebo (n=36) over 24 weeks (3 saturating doses followed by 5 maintenance doses). Concomitant use of riluzole and/or edaravone was allowed; at baseline, 62% of patients were taking riluzole, while 8% of patients were taking edaravone.

Over 28 weeks, participants in the VALOR study who were part of the primary analysis population (n=60) who received tofersen experienced a slowing of functional loss as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale ( ALSFRS-R ) from baseline compared to participants in the placebo group, although the difference between groups was not statistically significant (adjusted difference of means tofersen - placebo [95% CI] 1.2 [-3.2, 5.5]). In the overall intention-to-treat (ITT) population (n=108), tofersen-treated participants experienced a 55% reduction in plasma NfL levels compared with a 12% increase in participants receiving placebo (difference in geometric mean ratios for tofersen to placebo: 60%; nominal p<0.0001). In addition, SOD1 protein levels in cerebrospinal fluid, an indirect measure of treatment effect, were reduced by 35% in the tofersen-treated group compared to 2%
in the corresponding placebo-treated group (difference in geometric mean ratios for tofersen to placebo: 34%; nominal p<0.0001).

In an interim analysis conducted after 52 weeks in participants who completed the VALOR study and were enrolled in the Open Label Extension (OLE) follow-up study, a reduction in NfL was observed in previously placebo-treated participants who began tofersen treatment in the OLE study, similar to the reduction observed in tofersen-treated participants in the VALOR study. Compared with placebo/delayed treatment initiation, earlier initiation of the drug was associated with a trend toward reduction, worsening measures of clinical function(ALSFRS-R), respiratory strength (predicted percentage of vital capacity measured in a slow maneuver) and muscle strength ( HHD measure - megascore of hand-held dynamometry), although these were not statistically significant. Tofersen was also associated with a statistically insignificant trend toward a reduced risk of death or the need for continued use of mechanical ventilation. Exploratory analyses should be interpreted with caution, given the limitations of data collected outside of a controlled trial, which may be influenced by confounding variables.

The approval of the drug tofersen is based on 12-month integrated results from the VALOR study and the OLE study, comparing early initiation of tofersen (at the start of the VALOR study) with delayed initiation of tofersen (six months later, in OLE), which were published in The New England Journal of Medicine.

Source: press mat.