S/GSK : a next generation integrase inhibitor (INI) with limited or no-cross resistance to first generation INIs or other classes of anti-virals

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1 S/GSK : a next generation integrase inhibitor (INI) with limited or no-cross resistance to first generation INIs or other classes of anti-virals A. Sato 1, M. Kobayashi 1, T. Seki 1, C.W. Morimoto 1, T. Yoshinaga 1, T. Fujiwara 1, B.A. Johns 2, M.R. Underwood 3. 1 Discovery Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan. 2 GlaxoSmithKline Inc. Medicinal Chemistry, RTP, NC, USA. 3 GlaxoSmithKline Inc. Discovery Performance Unit, RTP, NC, USA. 8th European HIV Drug Resistance Workshop March 2010, Sorrento Italy

2 Chemical Structure of S/GSK Na + O O CH 3 F F H N O O N N H O Chemical Properties Chiral, non-racemic >98% ee MW: 419 g/mol (parent) pka (OH): 8.0

3 Inhibition of Recombinant HIV Integrase and HIV Replication by S/GSK and Clinically Relevant INIs INI Integrase, nm Strand tranfer IC 50 PBMC IC 50 Antiviral, nm Potency Shift with 100% HS PA IC 50 S/GSK Raltegravir Elvitegravir Inhibition of Different HIV Clades and Clinical Isolates by S/GSK Assay N Mean IC50 (nm) [range] HIV-1 Isolates in PBMCs (Clades A-G, O) [ ] HIV-1 Isolates in MDMs [ ] HIV-2 Isolates in PBMCs [ ] HIV-1 containing Integrase coding region from clade B isolates [ ] HIV-1 IIIB HIV-1 HXB

4 S/GSK Mean FC against Protease- Mutation SDMs (Site-Directed Molecular clones) Viruses Mean IC50 nm (Fold Change) S/GSK Amprenavir Ritonavir Wild type (NL432) M46I/I47V/I50V L24I/M46I/L63P /A71V/G73S/V82T (0.4) (6.1) (1.4) (0.4) (0.7) (14) Clinical Cut-offs FC (APV=2.0, RTV=2.5)

5 S/GSK Mean FC against RT- Mutation SDMs Viruses Mean IC50 nm (Fold Change) S/GSK Zidovudine Lamivudine Efavirenz Wild type (NL432) K103N (1.2) (1.2) (1.0) (39) M184V >10,000 (0.9) (0.8) (0.7) Y188L (1.5) (1.3) (1.2) (290) D67N/K70R /T215Y (1.1) (17) (4.8) (0.5) V75I/F77L >10,000 /F116Y/Q151M (0.9) (7.1) (1.2) Clinical Cut-offs FC ( ZDV=1.9, 3TC=3.5 EFV=3.0)

6 S/GSK , RAL and ELV Mean FC against RAL & ELV-related Single Mutation SDMs S/ GSK S/ GSK Raltegravir Elvit egravir Elvit egravir Raltegravir WT T66A T66I T66K E92I E9 2Q E92V G118S F121Y T124A E138K G140S Y143C Y143H Y143R P145S Q146R Q148H Q148K Q148R I151L S153F S153Y M154I N155H N155S N155T G193E

7 S/GSK , RAL and ELV Mean FC against Q148 and Additional Mutation SDMs Viruses Mean FC S/GSK Raltegravir Elvitegravir Q148H Q148K Q148R E138A/Q148R E138K/Q148H E138K/Q148K E138K/Q148R G140C/Q148R G140S/Q148H 2.6 >130 >890 G140S/Q148K G140S/Q148R FC < 10, 10 FC

8 S/GSK , RAL and ELV Mean FC against Y143, N155 and Additional Mutation SDMs Viruses Mean FC S/GSK Raltegravir Elvitegravir Y143C Y143H Y143R N155H L74M/N155H E92Q/N155H 2.5 > T97A/N155H Y143H/N155H N155H/G163K N155H/G163R N155H/D232N FC

9 S/GSK and RAL Mean FC against Clinical Isolates from RAL-failure Patients Fold Change Sequence No. S/GSK Raltegravir 44 N155H G140S,Q148R 7.6 >87 46 G140S,Q148R 19 >87 49 G140S,Q148H 7.3 >87 50 T97A,Y143C 1.2 >87 51 G140S,Q148H 3.0 >87 54 G140S,Q148H 3.8 >87 60 G140S,Q148H 15 >87 65 N155H T97A,Y143R 1.1 >81 73 N155H E138E/A, G140G/S, Q148Q/H 2.6 >81 86 E92E/Q, T97T/A, Y143R FC < 10, 10 FC

10 In vitro Passage Study Demonstrated the Potential for a Higher Genetic Barrier to Resistance of S/GSK (Initial conc. of Cpd) nM RAL(32nM) RAL(6.4nM) 572(6.4nM) 572(1.3nM) 572(0.26nM) nm Cpd nM 6.4nM Days Passage

11 Integrase Substitutions Generated by Passage in the Presence of S/GSK , RAL, or ELV Raltegravir ( 84 days) Elvitegravir (56 days) S/GSK (56 days) T124A Q148K* Q148R E138K/Q148K E138K/Q148R G140S/Q148R N17S/ Q148K /G163R G140C/ Q148K /G163R E138K/Q148K /G163R E92Q/ E138K/Q148K /M154I N155H /I204T V151I/N155H T124A/ V151I/N155H T66I E92Q T124A P145S Q148K Q148R T66I /T124A T66K /T124A E92V/T124A P145S/T124A Q146L/T124A Q148R /T124A T66I /V72A/A128T T66I/E92Q /T124A T66I /T124A/Q146L T124A T124A/S153F S/GSK (84 days) T124A S153Y T124A/S153Y L101I/T124A/S153F S/GSK (112 days) T124A S153Y T124A/S153Y L101I/T124A/S153F (FC=6 - >138) (FC=2-497) (FC= ) Red text indicates substitutions seen in clinical trials T124A is polymorphic and partially mixed in starting IIIB viruses S/GSK has low FC (<3) in activity against T124A, S153Y, L101I/S153F, and L101I/T124A/S153F SDMs.

12 Conclusions S/GSK demonstrates low FC (<5) in activity against all single mutants including RAL & ELV-related RVs. Most IN double to quintuple mutants have significantly lower FC to S/GSK compared with RAL and ELV. S/GSK exhibits limited cross resistance with INIresistant viruses. S/GSK exhibits no cross resistance with RTI- and PI-resistant viruses. S/GSK has a resistance profile distinct from RAL and ELV, and demonstrates the potential for a higher genetic barrier to resistance.

13 Summary of S/GSK : Next Generation INI Mean Change from Baseline in HIV-1 RNA (log 10 copies/ml) Dosing period Follow-up period (BL) Day (FU) 1.Lalezari J. et al. IAS 2009, Cape Town, abstract TUAB Min S, et al. IAS 2009, Cape Town, abstract WEPEA Song I, et al. IAS 2009, Cape Town, abstract WEPEB Sato A, et al. IAS 2009, Cape Town, abstract WEPEA Underwood M, et al. IAS 2009, Cape Town, abstract WEPEA Seki T, et al. CROI 2010, Poster abstract J mg 10 mg 50 mg PBO Only once daily, unboosted INI in clinical development 1 Low PK variability and predictable exposureresponse relationship with a low mg dose 2,3 Very strong antiviral activity in a ph2a study 1 Markedly different in vitro resistance profile with potential for higher genetic barrier to resistance 4,5,6

14 Acknowledgements Tamio Fujiwara Kazunori Ohno Tetsuji Itoh Teruhiko Taishi Takashi Kawasuji Brian Johns Andrew Spaltenstein Anh Nguyen Naoko Fujioka Akihiko Sato Tomokazu Yoshinaga Hiroshi Yoshida Yasunori Aoyama Satoshi Sakuma Yasuo Ida Ryuichi Kiyama John Eaddy Pam Golden Karen Prus Den Tsutae Nagata Julie Brandt Yoshihisa Goto Shuji Iwashita Mari Kuwabara Garrett Nichols Paul Hopkins Richard Henderson Masahiro Fuji Nelson Johnson John Roberts Scott Foster Dick Hazen Rob Ferris Ed Garvey Hidetoshi Myojyo Susan Witham Jason Weatherhead Khalida Shamim David Temelkoff Annelies Mallens Cynthia Edwards Mark Woodward Takahiro Seki Jim Bishop Jeanne Harrison Alan Millar Hitoshi Murai Norihiko Tanimoto Bill Spreen Melissa Rhodes Neil Shortman Renata Buckley Robert Cuffe Sherene Min Cindy Brothers Masatoshi Takada Mikiko Kanamori-Koyama Takeshi Funaki Ivy Song Christopher Stainsby Toru Ishibashi Mark Underwood Marty St Clair Chiaki Wakasa-Morimoto Ken Campbell Robin White Louise Martin-Carpenter Steve Piscitelli Jeff Lubrano Julie Borland Craig Sommerville Toshio Fujishita All patients enrolled in the clinical trials S/GSK is owned by Shionogi-GlaxoSmithKline Pharmaceuticals, LLC. Kazutoshi Horie Mitsuaki Machida Manabu Okada Andrew Roberson Matt Sharp Sherry Watson Frank DeMartin Tisha Cromwell Melody Courtney Betsy Williams Jane Yeo Peter Varlashkin Dan Todd Hideyuki Kitamura John Hughes Yu Lou Shigeru Miki Nancy Flack Dave Rudd Paul Trusty Ben Keane Lee Immins Norberto Quinones Tamio Fukushima Corina Engdahl Paul Savina Deb Steimers Christine Smith Cindy Wilson Jane Bethea David Jewell Kyoko Nagao Fran Martin Mari Kawamura Martha Anne Moore John Pottage Zhi Hong Susan Ford Akemi Suyama Masanori Kobayashi Julia Harris Sara Hughes Elizabeth Austin Tracy Cyr Debbie Thomas Shinobu Kawauchi Vani Vannapaggari Mounir Ait-Khalad Toshihiro Wajima Carolyn Goodwin Eri Kanaoka

15 S/GSK , RAL and ELV Mean FC against Q148 and Additional Mutation SDMs Viruses Mean FC S/GSK Raltegravir Elvitegravir E138A/S147G/Q148R E138K/G140S/Q148R 8.3 > G140S/Q148R/V201I 10 > T97A/G140S/Q148H 13 > E138K/G140S/Q148H G140S/Q148H/M154I 7.0 > E138K/G140S/Q148H/M154I 8.4 > V75I/E138K/G140S /Q148H/M154I 21 > FC < 10, 10 FC

16 S/GSK , RAL and ELV Mean FC against Other Mutation SDMs Viruses Mean FC S/GSK Raltegravir Elvitegravir T66I/L74M T66I/E92Q T66K/L74M F121Y/T125K I151L S153F S153Y L101I/S153F L101I/T124A/S153F FC < 10, 10 FC