`cholesterol
`G. Hardee, R. Geary, L. Tillman, J. Bradley, J. Su, S. Dokka, M. Wedel
` Isis Pharmaceuticals
`Purpose: To study the oral bioavailability (BAV) and pharmacology of second-generation oligonucleotide formulations upon
`repeated administration.
`Methods: Thirty-six healthy volunteers received an IV loading dose of 200 mg of ISIS 301012 on day 1 after which they
`received either oral ISIS 301012 or placebo once daily for 30 or 90 days. Six additional subjects received IV ISIS 301012 on
`a schedule modeled to mimic 10% oral BAV. The oral formulations used in this study utilized a controlled release of the
`penetration enhancer, sodium caprate, to enhance bioavailability. Previously, this formulation, optimized for another second-
`generation oligonucleotide, demonstrated 10-15% oral bioavailability and an acceptable safety profile in Phase I studies.
`Subjects were monitored for plasma (trough) drug levels and serum lipids weekly. Additionally, complete (24 hr) plasma PK
`profiles were conducted on the first and last oral dosing.
`Results: A mean oral bioavailability of 6% was observed. Maximal pharmacological responses were achieved on days 55 and
`69 with a statistically significant decrease of 12-15% apoB and commensurate reductions in LDL-C (p=0.005). The oral
`formulation was generally, well tolerated with mild, intermittent gastrointestinal symptoms noted.
`Conclusions: This study demonstrates that administration of ISIS 301012 by either the oral or the parenteral route reduces
`apoB, LDL-C and total cholesterol. While oral bioavailability was modest, averaging 6%, plasma and tissue levels proved
`sufficient to produce statistically significant and durable reductions in apoB and LDL-C in treated vs. control groups. These
`responses correlated with maximal plasma concentrations achieved in individuals after oral dosing. This study is the first to
`report significant gene down-regulation and pharmacological activity after oral administration of an antisense oligonucleotide
`and provides key information for future formulation enhancements.
`
`Grün. Exhibit 1089
`Grünenthal v. Antecip
`PGR2017-00022
`
`
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