| Size | Price | Stock | Qty |
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| 1mg |
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| Targets |
SOD1/Superoxide dismutase 1 mRNA
SOD1 (superoxide dismutase 1) mRNA. Tofersen is an antisense oligonucleotide that binds to SOD1 mRNA and recruits RNase H, leading to mRNA degradation and reduced SOD1 protein synthesis. |
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| ln Vitro |
Tofersen targets the SOD1 mRNA by binding to it through Watson-Crick base pairing with antisense oligonucleotides (ASOs). In order to degrade the targeted RNA, tofersen activates RNase H1[2].
Tofersen mediates RNase H-dependent degradation of SOD1 mRNA in vitro, reducing SOD1 protein levels in cell-based assays. The extent of knockdown is dose-dependent. |
| ln Vivo |
A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [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.
Conclusions: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.). [1] Tofersen has been evaluated in clinical trials for SOD1-ALS. It reduces SOD1 protein levels in cerebrospinal fluid (CSF) and shows slowing of disease progression in some patients. It received FDA approval for SOD1-ALS. |
| Enzyme Assay |
Antisense oligonucleotide binding assays: Tofersen binding to SOD1 mRNA is assessed using electrophoretic mobility shift assays (EMSA) or surface plasmon resonance (SPR). RNase H-mediated cleavage is measured by in vitro cleavage assays with purified RNase H and SOD1 mRNA.
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| Cell Assay |
Cells expressing SOD1 (e.g., fibroblasts from ALS patients) are treated with tofersen. SOD1 mRNA levels are measured by qPCR. SOD1 protein levels are measured by Western blot or ELISA. Cell viability is assessed using standard assays.
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| Animal Protocol |
Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.
Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.[1]
Transgenic mouse models of SOD1-ALS are administered tofersen intrathecally. SOD1 protein levels in spinal cord and CSF are measured. Motor function is assessed using rotarod and grip strength tests. Survival is recorded. |
| ADME/Pharmacokinetics |
Tofersen is administered intrathecally. As an ASO, it has a long half-life in CSF. It is metabolized by nucleases. The half-life in CSF is approximately several weeks.
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| Toxicity/Toxicokinetics |
Tofersen has been evaluated in clinical trials. Common adverse events include headache, back pain, and procedural pain. Serious adverse events include aseptic meningitis and hydrocephalus. The overall safety profile is acceptable for the treatment of SOD1-ALS.
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| References | |
| Additional Infomation |
Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial amyotrophic lateral sclerosis (ALS). Given the acquisition of toxic function in this dominant genetic disease, reducing SOD1 mRNA and protein levels is expected to provide therapeutic benefits. An early antisense oligonucleotide (ASO) targeting SOD1 was discovered and tested in a Phase I human clinical trial based on its mild protective effect in an animal model of SOD1 ALS. Despite encouraging safety data from this trial, the drug did not advance to the next stage of development due to progress in the design of other, more effective ASOs for central nervous system (CNS) applications. We developed a next-generation SOD1 ASO that more effectively reduces SOD1 mRNA and protein levels and extends the survival of SOD1G93A rats by more than 50 days and SOD1G93A mice by nearly 40 days. We demonstrated that the initial loss of complex muscle action potentials in SOD1G93A mice can be reversed after a single injection of SOD1 ASO. Furthermore, elevated serum levels of phosphorylated neurofilament heavy chains (a promising ALS biomarker) could be suppressed by SOD1 ASO therapy. These results suggest that a potent novel SOD1 ASO is ready for human clinical trials and indicate that the therapy can at least reverse some muscle responses. [2]
Tofersen (BIIB067; Qalsody) is an antisense oligonucleotide that mediates RNase H-dependent degradation of SOD1 mRNA. It received FDA approval for the treatment of SOD1-ALS. It is the first approved therapy targeting a genetic cause of ALS. |
| Molecular Weight |
7128.00
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| CAS # |
2088232-70-4
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| Sequence |
DNA, d([2'-O-(2-methoxyethyl)]m5rC-sp-[2'-O-(2-methoxyethyl)]rA-[2'-O-(2- methoxyethyl)]rG-sp-[2'-O-(2-methoxyethyl)]rG-[2'-O-(2-methoxyethyl)]rA-sp-Tsp-A-sp-m5C-sp-A-sp-T-sp-T-sp-T-sp-m5C-sp-T-sp-A-sp-[2'-O-(2-methoxyethyl)]m5rC-[2'-O-(2-methoxyethyl)]rA-sp-[2'-O-(2-methoxyethyl)]rG-[2'-O-(2-methoxyethyl)]m5rC-sp-[2'-O-(2-methoxyethyl)]m5rU)
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| Appearance |
Off-white to light yellow solid powder
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| Synonyms |
BIIB067; BIIB 067; Qalsody; BIIB-067; ISIS SOD1Rx; ISIS-SOD1Rx; ISIS SOD1Rx; Tofersen
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~100 mg/mL (~14.0 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (14.03 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1403 mL | 0.7015 mL | 1.4029 mL | |
| 5 mM | 0.0281 mL | 0.1403 mL | 0.2806 mL | |
| 10 mM | 0.0140 mL | 0.0701 mL | 0.1403 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03070119 | Active Recruiting |
Drug: Tofersen | ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation |
Biogen | March 8, 2017 | Phase 3 |
| NCT02623699 | Completed | Drug: Tofersen Drug: Placebo |
Amyotrophic Lateral Sclerosis | Biogen | January 20, 2016 | Phase 3 |
| NCT03764488 | Completed | Drug: 99mTc-MAG3-BIIB067 Drug: Tofersen |
Healthy Volunteers | Biogen | December 20, 2018 | Phase 1 |
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