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Golodirsen | CAS No: 1422959-91-8 | GMP-certified suppliers
A medication that targets Duchenne muscular dystrophy patients with specific gene mutations to potentially slow muscle degeneration and improve dystrophin protein production.
Therapeutic categories
Antisense Elements (Genetics)Antisense OligonucleotidesCompounds used in a research, industrial, or household settingDrugs that are Mainly Renally ExcretedLaboratory ChemicalsMolecular Probes
Generic name
Golodirsen
Molecule type
biotech
CAS number
1422959-91-8
DrugBank ID
DB15593
Approval status
Approved drug
ATC code
M09AX08
Primary indications
- Golodirsen is indicated to treat Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that would benefit from exon 53 skipping
- Continued FDA approval of this drug is contingent upon the results of clinical trials to confirm its benefit
Product Snapshot
- Golodirsen is an intravenous injectable oligonucleotide formulation
- It is primarily indicated for the treatment of Duchenne muscular dystrophy in patients with a specific DMD gene mutation amenable to exon 53 skipping
- Golodirsen has received FDA approval for use in the United States
Clinical Overview
Golodirsen is a morpholino antisense oligomer indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene amenable to exon 53 skipping. DMD is an X-linked genetic disorder characterized by progressive muscle degeneration and weakness, typically manifesting in early childhood and often resulting in loss of ambulation by early adolescence. The condition generally leads to premature mortality in the second or third decade of life due to cardiac and respiratory complications.
Pharmacodynamically, golodirsen functions by binding to exon 53 of dystrophin pre-mRNA, causing exclusion of this segment during mRNA splicing. This exon skipping restores the mRNA reading frame, enabling the production of a truncated but partially functional dystrophin protein. The induced dystrophin production is analogous to that observed in Becker muscular dystrophy, a milder phenotypic variant of dystrophinopathy. While the precise impact of golodirsen on motor function has not been definitively established, ongoing clinical trials aim to clarify its therapeutic benefit.
Pharmacokinetic data indicate that golodirsen is predominantly renally excreted. Though initial regulatory concerns focused on potential nephrotoxicity—common to morpholino antisense oligonucleotides—clinical trials have not demonstrated significant renal toxicity to date. Nonetheless, monitoring renal function during treatment is recommended.
Golodirsen received accelerated approval from the U.S. Food and Drug Administration in December 2019, contingent upon confirmatory clinical trials to validate clinical efficacy. It was developed by Sarepta Therapeutics. This approval pathway reflects the unmet medical need for targeted therapies addressing specific DMD mutations.
From a sourcing and quality perspective, procurement of golodirsen as an active pharmaceutical ingredient requires stringent adherence to regulatory standards for nucleic acid-based therapeutics. Ensuring high purity, absence of sequence impurities, and consistent batch-to-batch quality is critical. Manufacturers must also maintain rigorous controls for endotoxins and other contaminants inherent to oligonucleotide synthesis processes.
Pharmacodynamically, golodirsen functions by binding to exon 53 of dystrophin pre-mRNA, causing exclusion of this segment during mRNA splicing. This exon skipping restores the mRNA reading frame, enabling the production of a truncated but partially functional dystrophin protein. The induced dystrophin production is analogous to that observed in Becker muscular dystrophy, a milder phenotypic variant of dystrophinopathy. While the precise impact of golodirsen on motor function has not been definitively established, ongoing clinical trials aim to clarify its therapeutic benefit.
Pharmacokinetic data indicate that golodirsen is predominantly renally excreted. Though initial regulatory concerns focused on potential nephrotoxicity—common to morpholino antisense oligonucleotides—clinical trials have not demonstrated significant renal toxicity to date. Nonetheless, monitoring renal function during treatment is recommended.
Golodirsen received accelerated approval from the U.S. Food and Drug Administration in December 2019, contingent upon confirmatory clinical trials to validate clinical efficacy. It was developed by Sarepta Therapeutics. This approval pathway reflects the unmet medical need for targeted therapies addressing specific DMD mutations.
From a sourcing and quality perspective, procurement of golodirsen as an active pharmaceutical ingredient requires stringent adherence to regulatory standards for nucleic acid-based therapeutics. Ensuring high purity, absence of sequence impurities, and consistent batch-to-batch quality is critical. Manufacturers must also maintain rigorous controls for endotoxins and other contaminants inherent to oligonucleotide synthesis processes.
Identification & chemistry
| Generic name | Golodirsen |
|---|---|
| Molecule type | Biotech |
| CAS | 1422959-91-8 |
| UNII | 033072U4MZ |
| DrugBank ID | DB15593 |
Pharmacology
| Summary | Golodirsen is an antisense oligonucleotide that targets exon 53 of dystrophin pre-mRNA, promoting exon skipping to restore the dystrophin reading frame and induce production of a truncated, partially functional dystrophin protein. This mechanism addresses the genetic defect underlying Duchenne muscular dystrophy by enabling expression of dystrophin, a key muscle stabilizing protein. Pharmacodynamically, golodirsen modulates mRNA processing to increase dystrophin levels in affected muscle cells, with ongoing clinical evaluation of its impact on motor function. |
|---|---|
| Mechanism of action | The hallmark of Duchenne Muscular Dystrophy is the absence of the important muscle stabilizing protein, dystrophin, that is caused by a deletion mutation on the DMD (dystrophin) gene. This results in the production of a non-functional protein. Lack of dystrophin protein leads to progressive muscle weakness and degeneration. Golodirsen binds to exon 53 of dystrophin pre-mRNA on the DMD gene, excluding this protein coding unit during mRNA processing. The exclusion (or skipping) of exon 53 by golodirsen has the end result of changing out-of-frame mRNA to in-frame mRNA, inducing the production of dystrophin. The production of an imperfect dystrophin protein induced by golodirsen likely leads to a less severe condition, Becker Muscular Dystrophy (BMD), characterized by the production of a truncated dystrophin protein. Patients with BMD generally can expect a longer lifespan and improved quality of life. |
| Pharmacodynamics | Golodirsen masks genetic mutations that result in a cascade of events which treat Duchenne Muscular Dystrophy in about 8% of patients. Golodirsen indirectly induces the production of dystrophin, an important protein for muscle function. It is not yet confirmed whether motor function is improved by golodirsen, however, clinical trials are underway to examine its clinical benefits. **A note on nephrotoxicity** Though clinical trials have not yet confirmed that golodirsen is nephrotoxic, other morpholino antisense oligonucleotides have been known to cause nephrotoxicity. Ensure to monitor renal function during golodirsen therapy. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Dystrophin | Humans | inducer |
ADME / PK
| Absorption | This drug is given by the intravenous route, and is likely rapidly absorbed into the circulation. Pharmacokinetic studies for eteplirsen determined that Cmax occur within 1.1 to 1.2 hours of infusion initiation, after the administration of doses ranging from 0.5 mg/kg/week to 50 mg/kg/week. |
|---|---|
| Half-life | In a pharmacokinetic study, the elimination half-life of golodirsen was 3.4 hours with a standard deviation of 0.6 hours. |
| Protein binding | The protein binding of golodirsen ranges from 33 to 39%. |
| Metabolism | Golodirsen is not extensively metabolized. There were no metabolites detected in plasma or urine during a pharmacokinetic study. |
| Route of elimination | Golodirsen is excreted primarily as unchanged drug in the urine. |
| Volume of distribution | The volume of distribution at steady-state is approximately 668 mL/kg at 30 mL/kg dose of golodirsen. |
| Clearance | This drug is rapidly cleared from the systemic circulation, like other members of its drug class. The total clearance of eteplirsen, a drug from the same class, was 339 mL/h/kg after regular doses of 30 mg/kg/week. The clearance of golodirsen is likely similar. |
Formulation & handling
- Golodirsen is a biotech peptide administered intravenously as a sterile injectable solution. Handle under controlled conditions to maintain peptide stability and prevent degradation. Storage and reconstitution guidelines should be strictly followed to preserve biological activity.
Regulatory status
| Lifecycle | The API is marketed primarily in the United States with initial patent protection expiring in May 2021 and additional related patents set to expire by June 2025, indicating a transition phase toward increased generic competition and market maturity. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | Golodirsen is primarily marketed in the US with a single branded product, Vyondys 53, originating from one originator company. The patent portfolio extends up to mid-2025, indicating that generic competition is pending future patent expirations rather than currently established. There is limited presence outside the US market for this product. |
|---|
Safety
| Toxicity | No overdose information is available, however, renal toxicity has been seen with the administration of antisense oligomers, sometimes resulting in fatal glomerulonephritis. In the case of an overdose, it is advisable to provide supportive care and monitor renal function. LD50 information is currently unavailable for this drug. |
|---|
High Level Warnings:
- Potential for renal toxicity, including fatal glomerulonephritis, has been observed with antisense oligomer administration
- Renal function monitoring is recommended during handling and processing due to nephrotoxic risk
- LD50 data is unavailable
Golodirsen is a type of Antimetabolites
Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.
One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.
Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.
Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.
In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.
