Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs

Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making.

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Abstract 13307: An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans

Circulation ◽

10.1161/circ.142.suppl_3.13307 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Peter Gennemark ◽

Katrin Walter ◽

Niclas Clemmensen ◽

Dinko Rekic ◽

Catarina Nilsson ◽

...

Keyword(s):

Steady State ◽

Oral Administration ◽

Antisense Oligonucleotide ◽

Oral Delivery ◽

Permeation Enhancers ◽

Pcsk9 Inhibitors ◽

Liver Uptake ◽

Pcsk9 Inhibition ◽

Intestinal Permeation ◽

Intestinal Permeation Enhancers

Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation make this ASO highly potent. A single SC dose of 90 mg reduces PCSK9 by >90% in humans with elevated LDL-C (A), and a once monthly SC dose of 25 mg ([20, 30], 90% CI) is predicted to reduce PCKS9 by 80% at steady-state. To investigate the feasibility of oral administration, we developed an oral solid tablet wherein the ASO is co-formulated with a transient permeation enhancer. Repeated oral daily dosing of tablets to dogs resulted in a bioavailability of 7% in the liver (target organ), approximately 5-fold greater than the plasma bioavailability (B). Favourable liver uptake following oral administration is supported by similar bioavailability in plasma and kidney. Since the ASO is not active in rodents or dogs, we used a rat-specific GalNAc- Malat-1 ASO with the same chemistry to confirm target engagement. Intrajejunal administration resulted in ≥78% mRNA knockdown in the liver for single doses of 3-40 mg/kg. A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia.

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