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`1
`
`GIL2021
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00123
`
`

`

`3006
`
`NOTES
`
`J. VIROL.
`
`Luciferase compound assay. BM4-5 FEOcells were seeded
`into 96-well plates at a density of 10,000 cells per well in 100 pl
`medium. After allowing 4 h for attachment, compounds were
`added to wells at the specified concentrations. All conditions
`were runin triplicate. Cells and compoundswere incubated for
`48 h. The luciferase assay (Bright-Glo; Promega) wascarried
`out according to the manufacturer’s instructions. Luciferase
`activity was determined using a microplate luminometer (Ve-
`ritas microplate luminometer; Turner Biosystems). The rela-
`tive light units (RLU) for each condition were reported as the
`mean + the standard error of the mean for the three wells.
`
`Compounds tested. Compounds tested included two pep-
`tidomimetic HCV PIs, BILN 2061 (16) and a Vertex PI (19)
`(Vicki Sato, Vertex Pharmaceuticals, Cambridge, MA); a
`GlaxoSmithKline trans-lactam PI active-site mimic (2) (Karen
`Romines, GlaxoSmithKline, Research Triangle Park, NC); one
`nucleoside analog HCV RNA-dependent RNA polymerase
`inhibitor (RdRplI), 2’-C-methyladenosine (10) (William Lee,
`Gilead Sciences, Foster City, CA); one nonnucleoside GSK
`benzo-thiadiazine RNA polymerase inhibitor directed at
`the
`“thumb” region of the polymerase (Karen Romines, Glaxo-
`SmithKline) (9); and alpha interferon (Interferon-awA; Sigma-
`Aldrich).
`The 50% inhibitory concentration (IC5)) of each compound
`was determined independently and used to set the range of
`concentrations used for the synergy experiments. Each com-
`pound was tested singly and in combination at two twofold
`serial dilutions above and below the IC;,. The ratio of the two
`compounds tested remained fixed across the dosing range.
`Potential cytotoxicity of individual compounds andall combi-
`nations was assessed using a luminescent ATP-basedcell via-
`bility assay (Cell Titer-Glo; Promega).
`Data analysis. Determinations of compound interactions
`were based on the median-effect principle and the multiple
`drug effect equation as described by Chou and Talalay (6).
`Combination indices (CIs) were determined using Calcusyn
`(Biosoft) for each experimentat the IC59, ICj9, and IC4,levels.
`In total, 15 combinations were evaluated with from three to
`five replicates per condition; this yielded a total of 61 data
`points per CI level analyzed. A CI of <0.9 was considered
`synergistic, a CI of =0.9 or =1.1 was considered additive, and
`a CI of >1.1 was deemed antagonistic.
`Statistical analysis. At each of the three inhibitory concen-
`trations evaluated (ICs, IC7), and ICyg) the CIs in the three
`synergy groups were compared using a linear mixed-effects
`modelallowing for different meansin the three synergy groups
`and random effects for the individual drug combinations. The
`random effects were not significant (likelihood ratio test), in-
`dicating nostatistical difference in CI values between the an-
`tiviral compound combinationsin the same synergy group. The
`CI replicates were further compared between synergy groups
`by using the Wilcoxon ranktest.
`Synergy of small molecular inhibitors. Transfection of Huh-
`7.5.1 cells with BM4-5 FEO RNAyielded numerous (>50)
`G-418-resistant clones. Individual clones were expanded and
`assessed using the luciferase assay to determine the individual
`clones with highest RLU percell. Four clones yielded from
`30,000 to 50,000 RLU per 10,000 cells at 48 h (data not
`shown); these clones were expanded andusedforall subse-
`quent studies.
`
`TABLE 1. Activities of different small molecular inhibitors in the
`BM4-5 replicon
`HCV BM4-5
`replicon
`ICs(nM)*
`
`Compound
`
`Structure
`
`
`
`ysonbBbAq8102‘zzAveniqe4uo/Bio'wseiAly//:d}yyWo.pepeojuMoG
`
`IFN-alpha
`
`3.59 {U/ml = 0.41
`
`Po
`Vertex PI(19) Ay
`
`100,
`
`NK
`
`203.10 = 53.92
`
`BILN 2061 (16)
`
`9.444 0.88
`
`GSK PI (2)
`
`2’-C-methyladenosine(10) $00
`SO
`
`GSK NN} (9)
`
`308.6 + 28.9
`
`49722512
`
`3826 = 460.2
`
`
`
`“ The ICsq is the average + standard error of meanof the results from at least
`three independent experiments.
`
`The IC; for each of the individual compoundsis listed in
`Table 1. CI59, Cl4o, and Cly9 refer to the combination indexat
`the IC59, ICj9, and ICop, respectively, of each drug. All com-
`poundstested were additive (CI5, and Cl,,) or mildly syner-
`gistic (CI) with alpha interferon. Antagonism was not dem-
`onstrated for any combination of small molecular inhibitors,
`including compounds targeting the sameviral protein. Signif-
`icantly more synergy was demonstrated between compoundsin
`the group combining two small molecular inhibitors targeting
`the same viral enzyme (in this case NS3 protease) than be-
`tween the group of compounds combined with alpha interferon
`at both the Cl) (P = 0.043) and Clog (P = 0.017) levels. There
`was no significant difference between the groups at the Cl<,
`level (P = 0.108) (Fig. 1). Similarly, the group consisting of two
`inhibitors with different viral targets showedsignificantly lower
`combination indices than either of the other two groups, i.e.,
`compounds with interferon (P < 0.001 at all levels) or com-
`pounds with same mechanism of action (P = 0.038 and 0.037
`at the CI;, and Cl. levels, respectively). The comparison of
`ClIy98 between small molecular inhibitors with the same and
`different viral targets showed a trend toward a lower combina-
`tion index in the group with two compoundswith different viral
`targets (P = 0.056 at the Clog level) (Fig. 1). None of the
`compounds or combinations showed cytotoxicity at the con-
`centrations tested in the activity and synergy studies (data not
`shown).
`Small molecular inhibitors of the HCV protease and poly-
`
`2
`
`

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