Bojian Antisense Oligonucleotide Tofersen Treatment of ALS Phase 3 Clinical Failure

Compilenewborn

Recently, Biogen announced the top-line results of the key Phase 3 VALOR study of the antisense oligonucleotide drug tofersen
.

The study is evaluating tofersen for the treatment of amyotrophic lateral sclerosis (ALS) patients with superoxide dismutase 1 (SOD1) mutations

In addition, a pre-specified integration of data from the VALOR study and its ongoing open label extension study (OLE) reinforces these findings and shows that early initiation of tofersen therapy can lead to motor function and respiratory function in SOD1-ALS patients , Muscle strength and quality of life indicators decreased less
.

Most of the adverse events in the VALOR and OLE studies were mild to moderate in severity, including pain during the administration procedure, headache, limb pain, falls, and back pain

ALS is a progressive neurodegenerative disease with an average survival period of 3-5 years
.

The most common cause of death is respiratory failure

In view of the key unmet needs in this field, Biogen will extend the currently ongoing Early Access Program (EAP) eligibility to all SOD1-ALS patients.
In countries where local regulations allow such programs, the future acquisition of tofersen will be granted.
Guaranteed
.

The EAP program enables patients to obtain drugs for free before they are commercially licensed

VALOR research and OLE research:

VALOR research and OLE research:

Tofersen is an antisense drug and is currently being evaluated for its potential therapeutic effect on SOD1-ALS
.

Tofersen binds to SOD1 mRNA, allowing it to be degraded by RNase-H to reduce the synthesis of SOD1 protein

VALOR is a 28-week randomized, double-blind, placebo-controlled phase 3 study to evaluate the efficacy, safety and tolerability, pharmacodynamics and biological effects of tofersen (100mg) in adult patients with SOD1 mutation-related ALS Marker effect
.

In the study, a total of 108 patients were randomized (n=72 into the tofersen 100mg group, n=36 into the placebo group)

The OLE study is a phase 3 study for patients who have completed the VALOR study
.

Of the 108 patients in the VALOR study, 95 entered the OLE study

Top-line results:

Top-line results:

The results of the VALOR study showed that in the primary analysis (rapidly progressing) population, the primary efficacy endpoint of the total ALSFRS-R score from baseline to week 28 did not reach a statistically significant difference
.

In the multiple secondary and exploratory measurements of biological activity and clinical function (including motor function, respiratory function, and quality of life), trends in favor of tofersen can be observed

In the first key secondary endpoint: total CSF SOD1 protein (a marker involved in the target) compared to baseline changes, the difference between the tofersen group and the placebo group was 38 in the fast-progressing population and the slow-progressing population, respectively %, 26%
.
Plasma neurofilament light chain (NfL) is a potential marker of neuronal degeneration, in terms of the second key secondary endpoint of the baseline change of plasma neurofilament light chain (NfL): in the rapid progressing population and the slow progressing population, the tofersen group The differences observed in the placebo group were 67% and 48%, respectively
.

In the rapidly progressing population, the measurement results of respiratory function (slow vital capacity [SVC]; prediction difference=7.
9%) and muscle strength (hand-held dynamometer [HHD]; difference=0.
02) are beneficial to tofersen
.
Similar trends were observed in the outcome measures of disease severity, quality of life, and fatigue reported by multiple exploratory patients
.
Due to the small number of events that occurred within 28 weeks, the median time to event in survival analysis cannot be estimated
.

In addition, with the extension of the OLE study follow-up, early tofersen initiation of treatment continued to slow down the decline in clinical function indicators for the entire population
.

In the VALOR study, the most common adverse events (AE) in patients treated with tofersen were pain during the administration procedure, headache, limb pain, falls, and back pain
.
The severity of most adverse events in VALOR and OLE was mild to moderate
.
In VALOR, 18.
1% of patients treated with tofersen and 13.
9% of patients treated with placebo had serious adverse events
.
In the tofersen group, 5.
6% of patients discontinued treatment due to adverse events
.
No patients in the placebo group discontinued the drug due to adverse events
.
In the VALOR and OLE study, 4.
8% of patients treated with tofersen reported serious neurological events, including 2 cases of myelitis (2.
0%)
.
In the VALOR study, there was one death report in the tofersen group, which was determined to be unrelated to tofersen
.

Reference source: Biogen Announces Topline Results from the Tofersen Phase 3 Study and its Open-Label Extension in SOD1-ALS