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General Description:

Onasemnogene abeparvovec, identified by CAS number 1922968-73-7, is a notable compound with significant therapeutic applications. Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy that has been approved by the FDA in May 2019 for the treatment of infant patients (less than 2 years of age) with spinal muscular atrophy (SMA) and a specific mutation in the survival motor neuron 1 (SMN1) gene. SMA is a rare genetic disease that affects the survival and function of motor neurons, leading to debilitating and often fatal muscle weakness. As there is no cure for SMA, onasemnogene abeparvovec is a disease-modifying agent that decelerates the disease progression, improves motor function, and manages the symptoms. The use and effectiveness of onasemnogene abeparvovec in patients with advanced SMA, such as those with complete paralysis of the limbs and permanent dependence on ventilators, has not been evaluated. Onasemnogene abeparvovec is the first gene therapy that was approved for this indication in the USA. is another gene therapy that is currently approved by the FDA for the treatment of SMA in pediatric and adult patients. Developed by AveXis, a Novartis company, onasemnogene abeparvovec is commonly marketed as Zolgensma®, which is available as a single-dose intravenous infusion. Onasemnogene abeparvovec for therapeutic use and marketing is currently being assessed by the EU and an intrathecal formulation of the drug is currently undergoing clinical development in the USA.

Indications:

This drug is primarily indicated for: Onasemnogene abeparvovec is indicated for the treatment of pediatric patients less than 2 years of age (neonatal and infant patients) with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Onasemnogene abeparvovec undergoes metabolic processing primarily in: There is limited pharmacokinetic information on onasemnogene abeparvovec. The viral vector and the survival motor neuron (SMN) protein are expected to undergo normal nonspecific cellular degradation. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Onasemnogene abeparvovec are crucial for its therapeutic efficacy: There is limited pharmacokinetic information on onasemnogene abeparvovec. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Onasemnogene abeparvovec is an important consideration for its dosing schedule: There is limited pharmacokinetic information on onasemnogene abeparvovec. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Onasemnogene abeparvovec exhibits a strong affinity for binding with plasma proteins: There is limited pharmacokinetic information on onasemnogene abeparvovec. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Onasemnogene abeparvovec from the body primarily occurs through: There is limited pharmacokinetic information on onasemnogene abeparvovec. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Onasemnogene abeparvovec is distributed throughout the body with a volume of distribution of: There is limited pharmacokinetic information on onasemnogene abeparvovec. When biodistribution was evaluated in autopsy studies, the highest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Onasemnogene abeparvovec is a critical factor in determining its safe and effective dosage: There is limited pharmacokinetic information on onasemnogene abeparvovec. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Onasemnogene abeparvovec exerts its therapeutic effects through: Onasemnogene abeparvovec is a gene therapy that restores the levels of SMN protein in the spinal cord to promote the survival and function of motor neurons. Acute serious liver injury and elevated aminotransferases were observed with the treatment of onasemnogene abeparvovec in clinical trials. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Onasemnogene abeparvovec functions by: Spinal muscular atrophy is a genetic disorder caused by mutations in the SMN gene, which encodes the SMN protein. SMN protein is found ubiquitously but it is highly expressed in the spinal cord where it is responsible for the survival and maintenance of specialized nerve cells called motor neurons. SMN1 and SMN2 genes encode the SMN protein but many mutations in the SMN1 gene have been found to cause spinal muscular atrophy, as SMN1 is the primary gene responsible for functional production of SMN protein. A common mutation that causes spinal muscular atrophy involves a bi-allelic deletion of exon 7 in the SMN1 gene. The number of copies of the SMN2 gene varies among individuals: while higher number of SMN2 gene copies may protect against SMN protein deficiency caused by SMN1 gene mutations, it is generally proposed that the bi-allelic mutation in the SMN1 gene cannot be compensated by the SMN2 gene. The mutation results in insufficient SMN protein expression and inefficient assembly of the machinery needed to process pre-mRNA for motor neuron development and survival. Spinal muscular atrophy involves a progressive degeneration and loss of lower motor neurons, leading to muscle weakness and atrophy. Onasemnogene abeparvovec is gene therapy that consists of a recombinant self-complementary adeno-associated virus serotype 9 (AAV9) as a gene delivery vector, which contains a transgene encoding the human survival motor neuron (SMN) protein. AAV9 is commonly used in gene therapy applications because it is capable of crossing the blood-brain barrier and transducing neurons in the CNS. After administration, this viral vector is shed and a copy of the gene encoding the human SMN protein is delivered, leading to cell transduction and expression of the SMN protein. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Onasemnogene abeparvovec is categorized under the following therapeutic classes: Adeno-associated Viral Vector Therapies, Amino Acids, Peptides, and Proteins, Biological Products, Cellular and Gene Therapy, Complex Mixtures, Genetic Therapy, Hepatotoxic Agents, Musculo-Skeletal System, Proteins, Recombinant Proteins. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.