Volanesorsen

Volanesorsen is an antisense oligonucleotide designed to inhibit the formation of apoC-III, a protein that is recognised to regulate both triglyceride metabolism and hepatic clearance of chylomicrons and other triglyceride-rich lipoproteins. The selective binding of volanesorsen to the apoC-III messenger ribonucleic acid (mRNA) within the 3′ untranslated region at base position 489-508 causes the degradation of the mRNA. This binding prevents translation of the protein apoC-III, thus removing an inhibitor of triglyceride clearance and enabling metabolism through an LPL-independent pathway.

Pharmacodynamic effects

Effects of volanesorsen on lipid parameters

In APPROACH, the Phase 3 clinical study in patients with FCS, volanesorsen reduced fasting triglycerides, total cholesterol, non-HDL cholesterol, apoC-III, apoB-48, and chylomicron triglyceride levels and increased LDL-C, HDL-C, and apoB.

Mean baseline and percent change in lipid parameters from baseline to month 3:

Cardiac Electrophysiology

At a drug concentration 4.1 times the peak drug plasma concentrations (C_max) of the maximum recommended dose (285 mg subcutaneous injection), volanesorsen did not prolong the heart-rate corrected QT (QTc) interval.

Absorption

Following subcutaneous injection, peak plasma concentrations of volanesorsen are typically reached in 2 to 4 hours. The absolute bioavailability of volanesorsen following a single subcutaneous administration is approximately 80% (most likely higher because an AUC of 0 to 24 hours was used and volanesorsen has a half-life of >2 weeks).

Following a dose of 285 mg once weekly in patients with FCS, the estimated geometric mean (coefficient of variation % of geometric mean) steady-state C_max is 8.92 µg/ml (35%), AUC_0-168h is 136 µg*h/ml (38%), and C_trough is 127 ng/ml (58%) in patients who remain negative for anti-drug antibody. An alternative dosing regimen of 285 mg volanesorsen every two weeks results in a C_trough,ss of approximately 58.0 ng/ml with C_max and AUC similar compared to the once weekly dosing regimen.

Distribution

Volanesorsen was rapidly and widely distributed to tissues following subcutaneous or intravenous administration in all species evaluated. The estimated steady-state volume of distribution (Vss) in patients with FCS is 330 L. Volanesorsen is highly bound to human plasma proteins (>98%) and the binding is concentration independent.

In vitro studies show that volanesorsen is not a substrate or inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptides (OATP1B1, OATP1B3), bile salt export pump (BSEP), organic cation transporters (OCT1, OCT2), or organic anion transporters (OAT1, OAT3).

Biotransformation

Volanesorsen is not a substrate for CYP metabolism, and is metabolised in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases. Unchanged volanesorsen is the predominant circulating component.

In vitro studies indicate that volanesorsen is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 or inducer of CYP1A2, CYP2B6, or CYP3A4.

Elimination

Elimination involves both metabolism in tissues and excretion in urine. Urinary recovery of the parent drug was limited in humans with <3% of administered subcutaneous dose recovered within 24 hours post dose. The parent drug and 5- to 7-mer chain-shortened metabolites accounted for approximately 26% and 55% of oligonucleotides recovered in urine, respectively. Following subcutaneous administration, terminal elimination half-life is approximately 2 to 5 weeks.

In animals, elimination of volanesorsen was slow and occurred mainly via urinary excretion, reflecting rapid plasma clearance principally to tissues. Both volanesorsen and shorter oligonucleotide metabolites (predominantly 7-mer metabolites (generated either from 3′-deletions or 5′-deletions)) were identified in human urine.

Linearity / non-linearity

Single- and multiple-dose pharmacokinetics of volanesorsen in healthy volunteers and patients with hypertriglyceridemia have shown that the C_max of volanesorsen is dose-proportional over a dose range of 100 to 400 mg and the AUC is slightly more than dose-proportional over the same dose range. Steady-state was reached approximately 3 months after starting volanesorsen. Accumulation in C_trough was observed (7- to 14-fold) and little or no increase in C_max or AUC was observed following weekly SC administration over a dose of 200 to 400 mg. Some accumulation in AUC and C_max was observed for the 50 to 100 mg dose. Since the administered dose will be 285 mg every two weeks, or 142.5 mg weekly, little increase in C_max or AUC is expected upon multiple dosing in the clinical setting.

Special Populations

Renal impairment

A population pharmacokinetic analysis suggests that mild and moderate renal impairment has no clinically relevant effect on the systemic exposure of volanesorsen. No data are available in patients with severe renal impairment.

Hepatic impairment

The pharmacokinetics of volanesorsen in patients with hepatic impairment is unknown.

Age, sex, weight, and race

Based on the population pharmacokinetic analysis, age, body weight, sex, or race has no clinically relevant effect on volanesorsen exposure. There are limited data available in subjects >75 years of age.

Anti-volanesorsen antibody formation affecting pharmacokinetics

The formation of binding antibodies to volanesorsen appeared to increase total C_trough by 2- to 19-fold.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity or toxicity to reproduction and development.

Dose and time-dependent reductions in platelet counts were observed in Cynomolgus monkey repeated dose studies. The decrease was gradual, self-sustaining and did not decrease to adverse levels. In individual monkeys, severe thrombocytopenia was noted in the 9 month study of drug treated groups at clinically relevant exposures and has also been observed in clinical studies. The decrease in platelet counts was not acute and decreased to below 50,000 cells/μl. Platelet counts recovered after cessation of treatment, but decreased again below 50,000 cells/μl after treatment was resumed in some monkeys. Decreased platelet counts were also observed in rodent repeated dose studies. A mode of action for the observed thrombocytopenia is currently not known.

In nonclinical studies, levels of volanesorsen in milk were very low in lactating mice. The concentrations in breast milk of mice were >800 fold lower than effective tissue concentrations in maternal liver. Due to the poor oral bioavailability of volanesorsen, it is considered unlikely that these low milk concentrations would result in systemic exposure from nursing.