NAV

Tofersen

Identification

Summary

Tofersen is an antisense oligonucleotide indicated for the treatment of adult amyotrophic lateral sclerosis caused by SOD1 mutation.

Brand Names
Qalsody
Generic Name
Tofersen
DrugBank Accession Number
DB14782
Background

Tofersen is under an intrathecally administered antisense oligonucleotide targeting the mutated SOD1 gene that causes amyotrophic lateral sclerosis (ALS).4 Although there were various causes of ALS, 2% of ALS cases are due to SOD1 mutations, with more than 200 SOD1 mutations documented.2,3 Tofersen was granted accelerated approval from the FDA on April 25, 2023, as the first treatment for adults with ALS caused by SOD1 mutation.5 Continual FDA approval is contingent on clinical benefits from ongoing trials, particularly the Phase 3 ATLAST study in people with presymptomatic SOD1-ALS.5

Tofersen demonstrated efficacy in reducing the concentration of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks, although the ALS Functional Rating Scale–Revised did not improve.1 However, it could potentially be due to the short timeframe of tofersen treatment, and more longterm trials are being conducted to confirm this hypothesis.1

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
Synonyms
  • Antisense Oligonucleotide Inhibitor Of The Expression Of Superoxide Dismutase 1 Gene
  • 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-T-SP-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))R
  • IONIS SOD1Rx
  • Tofersen
External IDs
  • BIIB 067
  • BIIB067
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Pharmacology

Indication

Tofersen is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on the reduction in plasma neurofilament light chain (NfL) observed in patients treated with tofersen. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAmyotrophic lateral sclerosis (als)•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

At Week 28 in Study 1 Part C, a reduction in total CSF SOD1 protein of 35% (geometric mean ratio to baseline) in the tofersen-treated group versus a 2% decrease from baseline in the corresponding placebo subjects in the ITT population was observed (difference in geometric mean ratios for tofersen to placebo: 34%; nominal p<0.0001).4

Plasma NfL, a blood-based biomarker of axonal injury and neurodegeneration, was evaluated in Study 1 Part C in SOD1-ALS patients. At Week 28, mean plasma NfL was reduced by 55% (geometric mean ratio to baseline) in the tofersen-treated subjects compared to a 12% increase with placebo in intent-to-treat (ITT) population (difference in geometric mean ratios for tofersen to placebo: 60%; nominal p<0.0001). Plasma NfL declined until approximately Day 113, after which the reductions were sustained. The reductions in phosphorylated neurofilament heavy chain (pNfH) were similar compared to reductions in NfL, as were reductions in CSF compared to plasma.4

At the maximum approved recommended dosing regimen, tofersen does not prolong the QTc interval to any clinically relevant extent.4

Mechanism of action

Tofersen is an antisense oligonucleotide that causes degradation of SOD1 mRNA through binding to SOD1 mRNA, which results in a reduction of SOD1 protein synthesis.4

TargetActionsOrganism
ASuperoxide dismutase 1 (SOD1)
antisense oligonucleotide
Humans
Absorption

Intrathecal administration of tofersen into the CSF allows tofersen to be distributed from the CSF to central nervous system tissues. The maximum CSF trough concentration occurred at the third dose, which was the last dose of the loading period. There was little to no accumulation for CSF tofersen with monthly dosing after the loading phase. Tofersen is transferred from CSF into the systemic circulation, with a median time to maximum concentration (Tmax) plasma values ranging from 2 to 6 hours. There was no accumulation in plasma tofersen exposure following monthly maintenance dosing.4

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Tofersen is expected to be metabolized through exonuclease (3'- and 5')-mediated hydrolysis and is not a substrate for, or inhibitor, or inducer of CYP450 enzymes.4

Route of elimination

The primary route of elimination has not been characterized.4

Half-life

The effective half-life in CSF is estimated to be 4 weeks.4

Clearance

Not Available

Adverse Effects
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Toxicity

Studies to assess the carcinogenic potential of tofersen have not been conducted.4

Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.4

In a study to assess effects on fertility and reproductive function, tofersen (0, 3, 10, 30 mg/kg) was administered every other day to male and female mice prior to and during mating and continuing in females to gestation day (GD) 7. Adverse effects on male reproductive organs (seminiferous tubular degeneration, seminiferous tubule dilatation, spermatid retention, apoptosis of epithelial cells, increased cellular debris in the testes, and hypospermia in the epididymis) were observed at the highest dose tested; however, there were no adverse effects on functional endpoints. Plasma exposure at the no-effect dose (10 mg/kg) for adverse effects on male reproductive organs was approximately 2 times that in humans at the recommended human dose of 100 mg.4

Subcutaneous administration of tofersen (0, 3, 10, 30 mg/kg) every other day to pregnant mice during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure at the highest dose tested (30 mg/kg) was approximately 4 times that in humans at the recommended human dose (RHD) of 100 mg.4

Subcutaneous administration of tofersen (0, 3, 10, 30 mg/kg) every other day to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure at the highest dose tested (30 mg/kg) was approximately 20 times that in humans at the RHD.4

Subcutaneous administration of tofersen (0, 3, 10, or 30 mg/kg) every other day to male and female mice prior to and during mating and continuing in females throughout organogenesis resulted in no adverse effects on pre- or postnatal development. Plasma exposures at the highest dose tested (30 mg/kg) were approximately 4 times that in humans at the RHD.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
QalsodyInjection100 mg/15mLIntrathecalBiogen Inc.2023-04-25Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
2NU6F9601K
CAS number
2088232-70-4

References

General References
  1. Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S: Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705. [Article]
  2. Huai J, Zhang Z: Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants. Front Neurol. 2019 May 21;10:527. doi: 10.3389/fneur.2019.00527. eCollection 2019. [Article]
  3. Bali T, Self W, Liu J, Siddique T, Wang LH, Bird TD, Ratti E, Atassi N, Boylan KB, Glass JD, Maragakis NJ, Caress JB, McCluskey LF, Appel SH, Wymer JP, Gibson S, Zinman L, Mozaffar T, Callaghan B, McVey AL, Jockel-Balsarotti J, Allred P, Fisher ER, Lopate G, Pestronk A, Cudkowicz ME, Miller TM: Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry. 2017 Feb;88(2):99-105. doi: 10.1136/jnnp-2016-313521. Epub 2016 Jun 3. [Article]
  4. FDA Approved Drug Products: QALSODY (tofersen) injection, for intrathecal use [Link]
  5. FDA approves QALSODY™ (tofersen) as the first treatment targeting a genetic cause of ALS [Link]
RxNav
2634995
Wikipedia
Tofersen

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAmyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation1
3CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
3RecruitingTreatmentAmyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation1
1CompletedBasic ScienceHealthy Volunteers (HV)1
Not AvailableApproved for MarketingNot AvailableAmyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntrathecal100 mg/15mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10968453No2021-04-062035-04-01US flag
US10669546No2020-06-022035-04-01US flag
US10385341No2019-08-202035-04-01US flag

Properties

State
Liquid
Experimental Properties
Not Available

Drug created at May 20, 2019 14:26 / Updated at July 18, 2023 22:57