Nanoformulations: Update from ViiV Healthcare. Cabotegravir: Long Acting HIV Integrase inhibitor

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1 Nanoformulations: Update from ViiV Healthcare Cabotegravir: Long Acting HIV Integrase inhibitor Bill Spreen, Pharm.D. Cabotegravir Medicines Development Leader, GlaxoSmithKline R&D 1

2 Cabotegravir Long-Acting (LA) Nanosuspension Development Journey and Future Prospects 1. LA-ART concept and formulation 2. LA-ART partnering a need for real compatibility 3. Preclinical and clinical studies in healthy volunteers 4. LA-ART development considerations 5. Progress report for HIV treatment and HIV PrEP clinical trials 6. Development next steps 2

3 CAB LA Injectable Nanosuspension for HIV Treatment and PrEP LA injectable drugs can provide successful approaches for chronic indications such as contraception 1 and schizophrenia 2,3 LA antiretroviral therapy (LA-ART) offers therapeutic potential but is complicated by need for combination ART, typically of 3 drugs Cabotegravir (CAB) + rilpivirine (RPV) are investigational LA agents aimed at advancing this concept; goals include: HIV Treatment CAB LA + RPV LA every 4 or 8 weeks as gluteal IM injection as a 2-drug maintenance regimen for HIV-infected patients HIV PrEP CAB LA monotherapy, dosed IM once every 3 months, to reduce risk of sexually acquired HIV-1 (combined with safer sex practices) 3 1- NEJM 366; J Clin Psychiatry 2013;74(10): Drugs in Context 2015; 4:

4 Cabotegravir Background Cabotegravir (CAB) is an investigational HIV integrase inhibitor and analogue of dolutegravir (DTG) CAB and DTG share similar preclinical profiles; CAB well-suited for formulation as a LA injection (200mg/mL nanosuspension) CAB monotherapy p.o. 5mg or 30mg/day produced >2log 10 decrease in HIV RNA -Spreen et al. HIV Clin Trials. 2013;14(5) CAB p.o. 10, 30, 60mg/day+ART efficacious through 96 weeks in ART-naïve patients -Margolis et al. CROI 2015; Seattle, WA. Poster 554LB.h 4

5 Cabotegravir Nanosuspension Drug crystal suspended in aqueous vehicle Nanomilled to increase surface area and drug dissolution rate Wet bead milling with terminal sterilization by gamma irradiation Higher drug loading vs. matrix approaches for lower inj. volume CAB LA 200mg/mL Component Function Cabotegravir free acid (d50 ~200 nm) Mannitol Surfactant System Water for Injection Active drug Tonicity agent Wetting/Stabilizer Solvent 5 R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9 5

6 Great Need for a Compatible Partner CAB + RPV attributes support LA approach Different MOA, resistance profiles, metabolic pathways Lack of drug interaction between CAB and RPV 1 Initial LA clinical trials support q4-8 week synchronous dosing schedule at practical injection volume alternative oral formulations to facilitate treatment initiation, oral-bridging and discontinuation strategies Well-established and favorable RPV safety profile 6 1- Ford S, AAC 2013:57,

7 7 Early Preclinical and Clinical Studies

8 CAB LA Single Injection Provides Detectable Drug in Plasma for 48 Weeks Mean Concentration-Time Profile (n=6/cohort) 100mg IM 200mg IM 400mg IM 800mg IM (split) 100mg SC 200mg SC 400mg SC (split) Plasma CAB (µg/ml) *PA-IC90 PA-IC90 (0.67 ug/ml) CAB 5mg/day p.o. Ctau = 0.6 ug/ml CAB LA apparent half-life ~40days versus CAB oral ~40hr half-life Time (weeks) 8 Spreen et al. JAIDS 2014; Aug 21, Epub

9 CAB LA Monthly or Quarterly Repeat Doses Exceed Minimum Target Plasma Levels in Healthy Adults Plasma GSK (µg/ml) Mean plasma concentration-time profile (n=10/cohort) 800mg IM LD, 200mg SC q4w x 3 800mg IM LD, 200mg IM q4w x 3 800mg IM LD, 400mg IM q4w x 3 800mg IM quarterly x 2 4* PA-IC90 (0.664µg/mL) 0 CAB 5mg/day po Ctau = 0.6 ug/ml Time (weeks) = q 28 day injection = q 84 day injection 9 9

10 CAB LA Injections Generally Well Tolerated Summary of Percent of Subjects with Injection Site Reaction (ISR) AE (n=98) Subjects with ISRs CAB IM (N=80) CAB SC (N=28) PBO IM (N=8) PBO SC (N=6) RPV IM (N=19) Any ISR 59 (74%) 27 (96%) 2 (25%) 3 (50%) 18 (95%) Pain 58 (73%) 24 (86%) 2 (25%) 2 (33%) 17 (89%) Erythema 15 (19%) 22 (79%) 0 1 (17%) 2 (11%) Nodule 11 (14%) 22 (79%) (16%) Warmth at injection site 6 (8%) 8 (29%) (5%) Induration 5 (6%) 7 (25%) (5%) Pruritus 4 (5%) 5 (18%) Ecchymosis (bruise) 2 (3%) 4 (14%) 0 1 (17%) 1 (5%) Other 5 (6%) 3 (11%) Swelling 1 (1%) 4 (14%) Injection site dryness 0 1 (4%) Median IM ISR durations ~5 days for both pain and erythema and ~22 days for nodules Majority of all ISR symptoms were mild (84%=Gr1; 16%=Gr2), without any Gr3 or ISR related WDs 40 subjects provided tolerability evaluations on scale of 1-5 (5 as very tolerable) for each injection on Days 1, 14 and 28. Overall, most subjects rated injections as very tolerable with means ranging between for each treatment Lou et al. ICAAC

11 CAB LA NHP Preclinical Proof of Principle for PrEP Rectal Vaginal Vaginal Drug+virus challenges Washout Drug+virus challenges Washout Drug+virus challenges Washout CAB LA CAB LA 8/8 protected CAB LACAB LA CAB LA 100 CAB LA CAB LA 6/8 protected Aviremic (%) GSK744 (n=6) Placebo controls (n=6) 8/8 infected 4/4 infected 25 p = Weekly SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques (viral challenge weekly 0-7) SHIV 162p3 300xTCID50 Intravaginal Challenge in Female Rhesus Macaques, with DMPA (viral challenge Week 1, 5 and 7) Weeks SHIV 162p3 50xTCID50 Intravaginal Challenge in Female Pigtail Macaques, no DMPA (biweekly viral challenges x 22) Andrews et al. 20 th CROI 2013 Andrews et al. 21 st CROI 2014 Radzio et al. 21 st CROI

12 CAB LA PrEP Activity Extended to Lower Drug Levels in NHP Rectal Challenge Model CAB LA 50mg/Kg at Week -1 CAB Plasma Levels >3x PAIC 90 result in 100% Protection, while 1x PAIC 90 are 97% Effective range of CAB (GSK744) exposure in POC study Open symbol point of infection SHIV 162p3 50xTCID50 Intrarectal Challenge in Female Rhesus Macaques (weekly viral challenge starting at Week 0) 12 Andrews et al., Science, Mar2014

13 CAB LA PrEP Activity Extended to Lower Drug Levels in NHP Vaginal Challenge Model PK Study 10 mg/kg x 2 CAB plasma levels >4x PAIC90 result in 98% protection, while 1-4x and <1x PAIC90 were similar to untreated controls 30 mg/kg x 2 50mg/Kg x 2 SIVmac xTCID50 Intravaginal Challenge in Female Rhesus Macaques, no DMPA (weekly viral challenge starting at Week 0) Spreen et al. CROI 2015; Seattle, WA. Poster 966LB 13

14 CAB has Similar Partitioning into Human and NHP Rectal, Cervical and Vaginal Tissues Studies used variety of CAB doses and sampling times - human study at ½ dose of projected PrEP dose All drug concentration assay work by LC/MS/MS at GSK Matrix Non-Human Primates Mean Ratio T:P (range) Human Subjects@ 400mg a Median Ratio T:P (range) Vagina 0.15 ( ) b 0.19; 0.28 (NQ 0.7) Cervix Rectum 0.14 ( ) b 0.09 (NQ 0.2) c 0.16; 0.20 (NQ 0.4) 0.13 ( ) b NQ; 0.08 (NQ 0.2) 0.21 ( ) d a. Single 400mg IM dose (1x 400mg or 2x 200mg): n=8 females; n=8 males (Spreen, JAIDS, 2014) b. Single 50mg/kg IM dose: n=6 female pigtail macaques, no DMPA (JG Garcia-Lerma, personal communication) c. Repeat 50mg/kg (n=8) IM doses in female rhesus macaques, with DMPA (Andrews, 21st CROI, 2014) d. Repeat 10mg/kg (n=8) or 30 mg/kg (n=4) IM doses in male rhesus macaques (Andrews, Science, 2014) 14

15 Cabotegravir Population PK Model: BMI and Gender influence LA absorption rate Two compartment model (n=346 p.o./la subjects; n=121 on LA) Covariate analysis by stepwise covariate method Age, Gender, Race, BMI, BSA, WT, HIV status, Route (PO/IM/SC), injections per dose Gender, BMI included in final model as statistically and clinically significant Gender Male Female BMI 50 th Percentile (10 th, 90 th ) (kg/m 2 ) 26.8 (22.8, 30.3) 26.3 (21.7, 30.4) Mean Estimate of Ka LA (h -1 ) by BMI Quantile (Relative Difference from 50% Ka LA) 10% 50% 90% (1.35) 35% (1.43) 43% (1.00) (1.00) (0.799) 20% (0.762) 24% 15 Ford et al. ICAAC 2014; Washington, DC. Abstract H-645.

16 16 LA-ART Development Considerations

17 LA-ART Development Considerations HIV Treatment (CAB+RPV) Establish viability of 2-drug maintenance regimen, currently not in any treatment guideline Create specific oral induction - injection maintenance strategy Establish transition-off strategies and manage long PK tail Deliver new aseptic manufacturing technology Progress CAB oral tablet and injectable products to simultaneous regulatory approval HIV PrEP (CAB) Establish oral lead-in, transition-off strategies and manage implications of long PK tail Entering era of active ARV control arms in registration studies PrEP trials to be conducted, in part, in resource-limited settings within clinical trial networks Developing world medical need is significant; must provide access to LDCs 17

18 Progress Report: HIV Treatment and PrEP 18

19 LATTE Study Design (oral 2-drug maintenance) Margolis et al. CROI 2015; Seattle, WA. Poster 554LB. 19

20 LATTE: HIV-1 RNA <50 c/ml by FDA Snapshot (ITT-E) Margolis et al. CROI 2015; Seattle, WA. Poster 554LB.h 20

21 LATTE 2 Study Design: First Study of CAB LA+RPV LA in HIV-infected Patients Induction Period N=309 subjects HIV RNA 1000 CD4 200 ART naïve Week - 20 Induction Period CAB 30 mg + ABC/3TC Orally Once Daily Week - 16 Week - 12 Week - 8 Week - 4 Add RPV 25 mg once daily Day 1 Randomize 2:2:1 Stratify VL prior to Wk -8 (<50 c/ml, yes/no) IM Q4W IM Q8W Continue Oral Week -4: Qualification Visit For Maintenance and add RPV 25 mg for all Subjects Day 1 : Start of Maintenance and Randomization Visit 21

22 LATTE 2 Study Design Maintenance and Extension Maintenance Period Extension Continue From Induction CAB LA 400mg IM + RPV LA 600mg IM Every 4 Weeks (Q4W) CAB Loading Dose CAB LA 600 mg IM + RPV LA 900 mg IM Every 8 Weeks (Q8W) Continue on or Switch to either Q4W or Q8W CAB Loading Doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC orally Once Daily RPV 25mg Key Study Events Day 1 Randomization W96 W102* W104 22

23 LATTE 2 - Update Fully enrolled mid-2014; first injection of all LA-ART regimen in Oct 2014 Oral CAB(30mg/d)+ABC/3TC induction period results consistent with prior data On track for primary analysis (Week 32) in 4Q 2015 Includes 20 week induction period + 32 week maintenance period Results may enable start of phase 3 program in

24 CAB LA PrEP Phase 2 Studies Safety and PK D1 W3 W4 W5 W17 W29 W41 W53 W65 W77 W81 1 CAB 30 mg PO qd Placebo PO qd CAB LA 800 mg IM q12 Weeks Placebo IM q12 Weeks Follow-Up Phase HIV negative, at-risk adults (excluding high risk) Drug PK sampling (blood plasma) in all study participants HPTN 077 (201103) n=176 (132 Active) 3:1 randomization 60% women US, Brazil, SA, Malawi Start date Jan 2015 GSK/ViiV ÉCLAIR (201120) n=120 (100 Active) 5:1 randomization At risk men US only Start date - March

25 PrEP Phase 2 Safety and PK - Update ECLAIR Study fully enrolled mid-2014 On track for primary analysis (Week 41) in 3Q 2015 HPTN 077 Study actively recruiting participants since 1Q 2015 Results anticipated in

26 26 Development Next Steps

27 CAB LA + RPV LA Treatment Phase 3 Program CAB+RPV oral regimen data through 96 weeks and LATTE-2 results, if successful, will enable Phase 3 treatment studies to start in 2016 ViiV/GSK and Janssen currently planning Phase 3 studies, considerations include: LATTE 2 type induction-maintenance Stable switch from PI, NNRTI or INI regimen 27

28 CAPRISA 014 Study Phase II trial to assess safety & acceptability of the long-acting injectable HIV integrase inhibitor, Cabotegravir (GSK ) in HIV uninfected women in South Africa Salim S. Abdool Karim (PI), Quarraisha Abdool Karim (Co-PI), & Leila Mansoor (Co-PI) D30 D1 D14 D28 W16 W28 W40 W52 W64 W76 W88 Follow up visits quarterly CAB 30 mg PO qd CAB LA 800 mg IM q12 Weeks Long-term Follow up PBO PO qd IM Placebo (20% Intralipid) q12 Weeks Long-term Follow up 4 week oral lead-in, safety results at Days 14 and 28 reviewed prior to LA injection N=630 high risk women, age yrs, DB, randomized 1:1 Pending regulatory approval, FSFV 4Q 2015, study continues until last subject completes 4 th injection (expected duration of months for subjects) Comprehensive counseling / condoms provided at every visit Long term follow up for 12 mos following LA injection(s) 28

29 CAB LA PrEP Program CAPRISA 014 in South African women HPTN 083 pivotal phase 2b/3 efficacy study in MSM and TGW in the Americas and Thailand Additional confirmatory efficacy study in at-risk women envisaged to follow HPTN 077 and CAPRISA

30 CONCLUSIONS - Cabotegravir LA Program Substantial progress to-date to develop and characterize safety, PK and PrEP potential of CAB LA With Janssen collaboration, LATTE study has delivered POC for 2-drug CAB+RPV maintenance regimen Key LATTE-2 data, to enable Phase 3, to readout by end-2015 CAB LA may play important role as: Half of first all-injectable q4-8 week LA-ART regimen Quarterly injectable PrEP intervention 30

31 Acknowledgments All Clinical Study Participants and Investigative Staff ViiV Healthcare/ GlaxoSmithKline R&D Kim Smith John Pottage Yun Lan Yueh Lee Moss Elizabeth Gould Sandy Griffith Britt Stancil Rennan Pan Alex Rinehart Gary Bowers Glenn Tabolt Paul Wannamaker Melinda Bomar Yu Lou Melissa Rhodes Zhi Hong Aaron Diamond AIDS Research Center / Tulane National Primate Research Center Chasity D. Andrews David D. Ho Martin Markowitz Cecilia Cheng-Mayer Agegnehu Gettie Mar Boente-Carrera Hiroshi Mohri Neal Padte Yaoxing Huang Faye Yu Kasi Russell-Lodrigue Rudolph P. Bohm, Jr NIAID RO1A Janssen R&D Peter Williams Herta Crauwels Joseph Mrus Rudolf Van Heeswijk Marita Stevens Kati Vandermeulen Martine Jacobs Katrien Verbruggen US CDC, Laboratory Branch, Division of HIV/AIDS Prevention Jessica Radzio Walid Heneine Leecresia Jenkins J. Gerardo García-Lerma James Mitchel David Garber Preclinical Microbicide & Prevention Research Branch, DAIDS, NIAID, NIH Jim Turpin James Cummins Fulvia Veronese Anabel Lowry 31