Tofersen

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Tofersen
Clinical data
Trade names Qalsody
AHFS/Drugs.com Monograph
MedlinePlus a623024
License data
Routes of
administration 		Intrathecal
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
Chemical and physical data
Formula C230H317N72O123P19S15
Molar mass 7127.85 g·mol−1

Tofersen, sold under the brand name Qalsody, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). [2] Tofersen is an antisense oligonucleotide that targets the production of superoxide dismutase 1, an enzyme whose mutant form is commonly associated with ALS. It is administered as an intrathecal injection. [2]

Contents

The most common side effects include fatigue, arthralgia (joint pain), increased cerebrospinal (brain and spinal cord) fluid white blood cells, and myalgia (muscle pain). [2]

Tofersen was approved for medical use in the United States in April 2023. [2] [3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication. [4]

Medical uses

Tofersen is indicated to treat people with amyotrophic lateral sclerosis (ALS) associated with a mutation in the superoxide dismutase 1 (SOD1) gene (SOD1-ALS). [2]

History

Tofersen was developed by Ionis Pharmaceuticals and was licensed to, and co-developed by, Biogen. [5] [6]

The effectiveness of tofersen was evaluated in a 28-week, randomized, double-blind, placebo-controlled clinical study in 147 participants with weakness attributable to amyotrophic lateral sclerosis and a superoxide dismutase 1 (SOD-1) mutation confirmed by a central laboratory. [2] The study randomly assigned 108 participants in a 2:1 ratio to receive treatment with either tofersen 100 mg (n = 72) or placebo (n = 36) for 24 weeks (three loading doses followed by five maintenance doses). [2] The participants were approximately 43% female; 57% male; 64% White; and 8% Asian. [2] The average age was 49.8 years (range from 23 to 78 years). [2]

The stage III clinical trial was conducted by the Neuroscience Institute and Sheffield Institute for Translational Neuroscience (SITraN), both at the University of Sheffield. [7]

The US Food and Drug Administration (FDA) granted the application for tofersen priority review, orphan drug, and fast track designations. [2] [4]

Society and culture

Economics

Only around 1-2% of ALS cases diagnosed in the United States each year carry the specific SOD1 mutation targeted by the drug. [8] Fewer than 500 patients a year are expected to be eligible for the drug, which is expected to cost over $100,000 for a year's treatment. [2] [9] [10] [11]

In February 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Qalsody, intended for the treatment of a type of amyotrophic lateral sclerosis caused by a defective superoxide dismutase 1 (SOD1) protein. [12] [13] The applicant for this medicinal product is Biogen Netherlands B.V. [12] The marketing authorisation in the EU was granted on 29 May 2024. [14]

Related Research Articles

<span class="mw-page-title-main">Superoxide dismutase</span> Class of enzymes

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O−
2) anion radical into normal molecular oxygen (O2) and hydrogen peroxide (H
2O
2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive O−
2.

<span class="mw-page-title-main">Biogen</span> Pharmaceutical company

Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. Biogen operates in Argentina, Brazil, Canada, China, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Sweden, and Switzerland.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

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<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">ALS</span> Rare neurodegenerative disease

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease in the United States, is a rare but terminal neurodegenerative disorder that results in the progressive loss of both upper and lower motor neurons that normally control voluntary muscle contraction. ALS is the most common form of the motor neuron diseases. ALS often presents in its early stages with gradual muscle stiffness, twitches, weakness, and wasting. Motor neuron loss typically continues until the abilities to eat, speak, move, and, lastly, breathe are all lost. While only 15% of people with ALS also fully develop frontotemporal dementia, an estimated 50% face at least some minor difficulties with thinking and behavior. Depending on which of the aforementioned symptoms develops first, ALS is classified as limb-onset or bulbar-onset.

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Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1). CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function. Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans. In humans the protein is encoded by the CCS gene.

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References

  1. ↑ "Qalsody- tofersen injection". DailyMed. 25 April 2023. Archived from the original on 8 May 2023. Retrieved 10 June 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 "FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene" (Press release). U.S. Food and Drug Administration (FDA). 25 April 2023. Archived from the original on 25 April 2023. Retrieved 25 April 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  3. ↑ "FDA Grants Accelerated Approval for Qalsody (tofersen) for SOD1-ALS, a Major Scientific Advancement as the First Treatment to Target a Genetic Cause of ALS" (Press release). Biogen. 25 April 2023. Archived from the original on 25 April 2023. Retrieved 25 April 2023– via GlobeNewswire.
  4. 1 2 New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
  5. ↑ Liu A (1 May 2019). "Biogen's antisense ALS drug shows promise in early clinical trial". FierceBiotech . Archived from the original on 2 February 2023. Retrieved 25 April 2023.
  6. ↑ Langreth R (22 March 2023). "Biogen's ALS Drug Gets Partial Backing From FDA Panel". Bloomberg News . Retrieved 25 April 2023.
  7. ↑ "FDA approves drug which helps to slow progression of rare form of MND". www.sheffield.ac.uk. 28 April 2023. Retrieved 16 May 2024.
  8. ↑ Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, et al. (January 2022). "SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity". Scientific Reports. 12 (1): 103. Bibcode:2022NatSR..12..103B. doi:10.1038/s41598-021-03891-8. PMC   8742055 . PMID   34996976.
  9. ↑ Constantino A (25 April 2023). "FDA grants accelerated approval for Biogen ALS drug that treats rare form of the disease". CNBC . Archived from the original on 25 April 2023. Retrieved 25 April 2023.
  10. ↑ Constantino A (22 March 2023). "FDA advisors vote against effectiveness of Biogen's ALS drug for rare and aggressive form of the disease". CNBC . Archived from the original on 10 April 2023. Retrieved 25 April 2023.
  11. ↑ Robins R (25 April 2023). "F.D.A. Approves Drug for Rare Form of A.L.S." The New York Times . Archived from the original on 25 April 2023. Retrieved 25 April 2023.
  12. 1 2 "Qalsody EPAR". European Medicines Agency (EMA). 22 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  13. ↑ "New treatment for rare motor neuron disease recommended for approval". European Medicines Agency (EMA) (Press release). 23 February 2024. Retrieved 24 February 2024.
  14. ↑ "Commission Implementing Decision" (PDF). 3 June 2024. Retrieved 5 June 2024.
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