Nusinersen

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to an intronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleic acid (pre-mRNA). By binding, the ASO displaces splicing factors, which normally suppress splicing. Displacement of these factors leads to retention of exon 7 in the SMN2 mRNA and hence when SMN2 mRNA is produced, it can be translated into the functional full length SMN protein.

SMA is a progressive neuromuscular disease resulting from mutations in chromosome 5q in the SMN1 gene. A second gene SMN2, located near SMN1, is responsible for a small amount of SMN protein production. SMA is a clinical spectrum of disease with disease severity linked to fewer numbers of SMN2 gene copies and younger age of symptom onset.

Single- and multiple-dose pharmacokinetics (PK) of nusinersen, administered via intrathecal injection, were determined in paediatric patients diagnosed with SMA.

Absorption

Intrathecal injection of nusinersen into the CSF allows nusinersen to be fully available for distribution from the CSF to the target central nervous system (CNS) tissues. Mean CSF trough concentrations of nusinersen accumulated approximately 1.4- to 3-fold after multiple loading and maintenance doses, and reached a steady state within approximately 24 months. Following intrathecal administration trough plasma concentrations of nusinersen were relatively low compared to the trough CSF concentration. Median plasma T_max values ranged from 1.7 to 6.0 hours. Mean plasma C_max and AUC values increased approximately dose proportionally over the evaluated dose range. There is no accumulation in plasma exposure measures (C_max and AUC) after multiple doses.

Distribution

Autopsy data from patients (n=3) show that nusinersen administered intrathecally is broadly distributed within the CNS achieving therapeutic levels in the target spinal cord tissues. Presence of nusinersen was also demonstrated in neurons and other cell types in the spinal cord and brain, and peripheral tissues such as skeletal muscle, liver, and kidney.

Biotransformation

Nusinersen is metabolized slowly and predominantly via exonuclease (3'- and 5')-mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes.

Elimination

The mean terminal elimination half-life in CSF is estimated at 135 to 177 days. The primary route of elimination is expected via urinary excretion of nusinersen and its metabolites.

Interactions

In vitro studies indicated that nusinersen is not an inducer or inhibitor of CYP450-mediated oxidative metabolism and therefore should not interfere with other medicinal products for these metabolic pathways. Nusinersen is not a substrate or inhibitor of human BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP transporters.

Characteristics in specific patient populations

Renal and hepatic impairment

The pharmacokinetics of nusinersen in patients with renal or hepatic impairment has not been studied. The effect of hepatic or renal insufficiency as covariates could not be thoroughly evaluated in the population PK model given the rarity of patients displaying clinically relevant liver or kidney insufficiencies. Population PK analyses revealed no apparent correlation between hepatic and renal clinical chemistry markers and inter-subject variability.

Race

The majority of patients studied were Caucasian. The population PK analysis suggests that race is unlikely to affect the PK of nusinersen.

arcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of nusinersen have not been performed.

Mutagenesis

Nusinersen demonstrated no evidence of genotoxicity.

Reproductive toxicity

Reproductive toxicology studies were conducted using subcutaneous administration of nusinersen in mice and rabbits. No impact on male or female fertility, or embryo-foetal development, or pre/post-natal development was observed.

Toxicology

In repeat-dose toxicity studies (14-weeks and 53-weeks) of intrathecal administration to juvenile cynomolgus monkeys, nusinersen was well tolerated. The exception was an acute, transient deficit in lower spinal reflexes which occurred at the highest dose levels in each study (3 or 4 mg per dose; equivalent to 30 or 40 mg per intrathecal dose in patients). These effects were observed within several hours post-dose and generally resolved within 48 hours.

In the 53-week intrathecal dosing study in cynomolgus monkeys no toxicity effects were seen at levels up to 14-fold the recommended annual clinical maintenance dose.