Nucleic Acid Therapeutics

  • Qalsody, Tofersen

Action: Antisense oligonucleotide (ASO) against superoxide dismutase 1 (SOD1) suppresses SOD1 expression.

The subjects are patients with familial ALS with SOD1 mutations*. 

Previous study results: No change was observed for the primary endpoint of ALSFRS-R (rate of symptom progression) in the double-blind period at six months (p=0.97).

Future extension studies hope to show the effect of the drug on slowing the rate of progression in the initial active drug group compared to that in the initial placebo group.


Clinical trial results: Phase III: There was no positive effect on the primary efficacy endpoint of change from baseline in ALSFRS-R total score at 28 weeks (double-blind period) in the primary analysis group (rapid progressive group) (placebo n=21; active n=39) (between-group difference 1.2; p=0.97). Serious neurologic adverse events (myelitis, meningitis, lumbar disc disease, intracranial hypertension, and papilledema) occurred in approximately 7% of patients with active drug. Zero occurred in the placebo group.(Miller et al., 2022)

However, a trend in favor of Tofelsen was observed for the secondary and exploratory endpoints (motor function, respiratory function, and quality of life) (Miller et al., 2021).

Tofelsen treatment significantly decreased the CSF neurofilament light chain (NLF) level, indicative of neuronal damage [60% reduction in active group and 20% increase in placebo group in the rapidly progressive group].

In an open-label extension study (after 12 months), ALSFR was 3.5 points (95% [CI]:0.4-6.7) and lung capacity (vital capacity) was 9.2% (95% CI:1.7-16.6) higher in the initial active drug group compared to that in the initial placebo group. Identifier: NCT03070119

Dosage: Monthly intrathecal injection

Side effects: In addition to adverse events related to lumbar puncture (headache, back pain, etc.), serious neurological events, including myelitis, occurred in the Tofelsen group.

Clinical Trials Status: On July 26, 2022, the FDA agreed to review a new drug application for tofersen. The application is based on a Phase 3 study that showed a greater reduction in neurofilament light chain NfL levels (a marker of transcellular damage) in the actual drug group. On 22 March 2002, the Advisory Committee stated that the reduction in neurofilaments was likely to indicate a clinical benefit for tofersen. However, the Committee voted that the data to date did not provide substantial evidence to support approval. However, the FDA granted accelerated approval (25 April 2023) on the basis that the reduction in neurofilaments was likely to provide a clinical benefit. For accelerated approval, efficacy must be demonstrated in subsequent studies.

A Phase III ATLAS clinical trial was initiated to test whether starting Tofelsen treatment in pre-onset individuals with SOD1 gene mutations can delay the onset of clinical symptoms. Identifier: NCT04856982 

Participants are being recruited.

Expected completion: August 2027

Remarks: Carriers with familial ALS who have a rapidly progressive SOD1 mutation, but are not yet symptomatic, are eligible.

Adeno-associated virus rh10 containing an anti-SOD1 microRNA (AAV-miR-SOD1)

Action: Adeno-associated virus rh10 containing an anti-SOD1 microRNA suppresses SOD1 expression by introducing a microRNA against SOD1 in the cerebrospinal fluid.

Results of previous studies: One case report: A rapidly progressive case of SOD1 mutation A5V* was treated (Mueller et al., 2020).

The patient required steroid therapy for AAV-associated meningitis. The patient died of respiratory failure 15.6 months after treatment and 20 months after onset.

Dosage: One intrathecal injection.

The treatment resulted in a 90% decrease in spinal SOD1 protein levels; however, it did not improve life expectancy.

Remarks: One case of non-rapidly progressive form (D91A-D91A mutation) was treated; however, the clinical course is not yet available.

ION363, Jacifusen

Action: Suppresses FUS expression by ASO. FUS is the third most common gene in familial ALS.

Clinical trial results: One case report; patient with FUS mutation P525L# (25 years old).

The patient had already experienced respiratory failure at the start of the treatment and was administered NTTV*. After starting treatment, ALSFRS seemed to decrease slowly, but respiratory failure and dysphagia progressed, and the patient died from complications approximately 1 year after starting treatment and 18 months after the onset of disease. (Korobeynikov et al., 2022)

#FUS mutation P525L averages 13.8 months after onset of respiratory failure (Zhou et al., 2020).

Dosage: Intrathecal injection (12 doses in 10 months)

Remarks: Pathologically, the abnormal accumulation of FUS protein in the spinal cord was reduced markedly; however, there was no improvement compared to that in the natural history of this mutation.

Clinical trial status: Phase III Identifier: NCT04768972

Recruiting participants

Expected completion: March 2024

BIIB078, Afinersen

Mode of action: Suppresses C9orf72* expression by ASO

Clinical trial results: ALSFRS-R (progression of symptoms) remained unchanged.

The Biogen Phase I trial BIIB078 showed safety but no clinical benefit (ALSFRS-R, %VC, etc.), and development was discontinued. Identifier: NCT03626012 

Dosage: Intrathecal injection (8 doses in 17 months)


Action: Suppresses C9orf72* expression by ASO.

Clinical Trial Results: Wave Life Sciences Phase I (NCT04931862) Cerebrospinal fluid showed a decrease in the abnormal protein (polyGP) expressed by the biomarker C9orf72 mutation. Identifier: NCT04931862 

Participants are being recruited

Expected completion: February 2023



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