Presentation #: OP221

Transcription

1 Pharmacokinetics, Safety and Tolerability of, a Novel Prodrug of Tenofovir, Administered as Ascending Multiple Doses to Healthy Volunteers and HBV-Infected Subjects Presentation #: OP22 Tawesak Tanwandee, MD, Somruedee Chatsiricharoenkul, MD, Pisit Tangkijvanich, MD, Satawat Thongsawat, MD, Wattana Sukeepaisarnjaroen, MD, Anchalee Avihigsanon, MD, Piyawat Komolmit, MD, and Teerha Piratvisuth, MD

2 Background Enhanced Efficacy and Safety Increased bioavailability by harnessing lipid uptake mechanisms Enhanced target tissue penetration Decreased renal and bone toxicity by reducing circulating TFV Enhanced Potency 97 fold more potent in HBV than TFV in vitro 200 fold more potent in HIV than TFV in vitro by acid sphingomyelinase

3 Overview Studies CRTV-CMX-02 and CRTV-CMX-20 Week Healthy Volunteers 2wk dose + 2wk follow-up DSMB Review CMX57 25mg qd (n=0) TDF 300mg qd (n=2) CMX57 50mg qd (n=0) TDF 300mg qd (n=2) CMX57 00mg (n=0) TDF 300mg qd (n=2) 50mg qd (n=8) Placebo (n=2) 00mg qd (n=8) Placebo (n=2) CMX57 0mg qd (n=0) TDF 300mg qd (n=2) DSMB Review 0mg qd (n=8) Placebo (n=2) 25mg qd (n=8) Placebo (n=2) CMX57 5mg qd (n=0) TDF 300mg qd (n=2) HBV Patients 4wk dose + 4wk follow-up 5mg qd (n=8) Placebo (n=2) 2

4 Study CTRV-CMX-02 and 20; Baseline Characteristics CMX-02 5 mg 0 mg 25 mg 50 mg 00 mg Placebo N= Gender Male(n):Female(n) 5:3 5:3 6:2 7: 6:2 8:2 Age [years] (6.9) 33.9 (6.8) 38.3 (6.8) 30.9 (0.8) 32.6 (7.8) 30.2 (8.8) Race - Asian (n) CMX-20 5 mg 0 mg 25 mg 50 mg 00 mg Viread N= Gender Male(n):Female(n) : 4:5 9: 6:4 6:4 3:5 Age [years] (3.5) 3.8 (9.3) 33.7 (0.0) 3.3 (7.6) 38.9 (7.7) 33.8 (8.5) Race - Asian (n) BMI [kg/m 2 ] 20.2 (0.5) 2.8 (2.) 23.5 (2.) 2.7 (3.0) 23.0 (3.7) 22.4 (3.4) ALT [U/L] 40 (5) 03 (84) 47 (34) 9 (75) 56 (58) 62 (9) HBV eag+/eag- 2:0 9:0 6:4 9: 2:8 5:3 Recruitment stopped due to lack of antiviral activity 2 Recruitment stopped at 9 tenofovir exalidex (not the planned 0) and 2 TFV due to logistical problems 3 Continuous variables are shown as Mean (SD) 3

5 : Healthy Volunteer Study CTRV-CMX-02; Number of subjects with AEs, by SOC Placebo System Organ Classification 5 mg 0 mg 25 mg 50 mg 00 mg Total NUMBER OF SUBJECTS Any AE Gastrointestinal Disorders 4 Infections and Infestations Injury, Poisoning and Procedural Complications Cardiac Disorders Nervous System Disorders 5 Respiratory, Thoracic and Mediastinal Disorder 3 50 subjects dosed No SAEs or discontinuations for AEs ECGs, vital signs, safety laboratory results show no patterns or any relationship to dose 4

6 C o n c e n t r a t i o n ( n g / m L ) Study CTRV-CMX-02 TXL PK D a y D a y m g 0 0 m g 2 5 m g 5 0 m g 0 0 m g DAY 4 5 mg 0 mg 25 mg 50 mg 00 mg n n=8 n=8 n=8 n=8 n=8 Cmax [ng/ml] (0.85) (8.05) (4.3) (42.6) (70.6) Tmax [h] Median (min, max) AUC 0-24 [ng-h/ml] t ½ [h] (, 4) 6.6 (2.7).2 (0.3) (2.5,4) 24.8 (7.2).38 (0.35) 3.5 (2.5, 0) 52.4 (3.2).64 (0.33) T i m e ( h r ) 3.0 (2, 6) 26 (90.9).84 (0.57) 3.0 (2,4) 285 (36) 2.4 (0.69) Approximately dose proportional PK Short half-life Supports QD dosing ~ 30% decrease in AUC with high fat meal No accumulation between Day and Day 4 5

7 C o n c e n t r a t i o n ( n g / m L ) Study CTRV-CMX-02 TFV PK D a y D a y m g 0. 0 m g 2 5 m g 5 0 m g 0 0 m g T i m e ( h r ) DAY 4 5 mg 0 mg 25 mg 50 mg 00 mg n n=8 n=8 n=8 n=8 n=8 Cmax [ng/ml] (0.5) (0.3) (2.0) (3.3) (6.4) Tmax [h] Median (min, max) AUC 0-24 [ng-h/ml] t ½ [h] (3, 0) 22.2 (9.2) 6.8 (.5) (4, 0) 26.3 () 4.4 (3.3) (6, 2) 78.7 (28.3) 20.9 (6.3) (3, 2) 63 (62.7) 27.4 (5.0) (6, 0) 256 (06) 26. (8.) Approximately dose proportional PK Supports QD dosing ~50% increase in AUC with high fat meal No accumulation between Day and Day 4 6

8 : HBV+ Patients Study CTRV-CMX-20; Number of subjects with AEs, by SOC System Organ Classification 5 mg 0 mg 25 mg 50 mg 00 mg Total Viread NUMBER OF SUBJECTS Any AE Blood and Lymphatic System Disorders Gastrointestinal Disorders 4 2 General Disorders and Administration Site Conditions 2 Infections and Infestations Injury, Poisoning and Procedural Complications Investigations Metabolism and Nutrition Disorders 2 Musculoskeletal Disorders Nervous System Disorders Reproductive System Disorders Skin Disorders Hepatobiliary Disorder Respiratory, Thoracic and Mediastinal Disorder 49 subjects dosed No SAEs or discontinuations for AEs ECGs, vital signs, safety laboratory results show no patterns or any relationship to dose Results are consistent with the disease and the study population 7

9 Study CTRV-CMX-20; TXL Pharmacokinetics DAY 28 5 mg 0 mg 25 mg 50 mg 00 mg n n=2 n=9 n=0 n=0 n=0 Cmax [ng/ml] Tmax [h] Median (min, max) AUC 0-24 [ng-h/ml] t ½ [h] 4.6 (--) 3.0 (3, 3.02) 5.6 ( -- ).4 ( -- ) Mean (SD) for all except Tmax 2.9 (9.5) 2.0 (0.8, 6) 26 (5.8).3 (0.48) 29.0 (5.5) 2.0 (, 2.5) 66.7 (37.6).7 (0.46) 5.3 (39.9).5 (, 2.5) 0 (8.9).5 (0.69) 02 (38.9) 2.3 (, 4) 33 (70) 2.6 (0.72) Approximately dose proportional PK with numerical increase at 00 mg Short half-life Supports QD dosing No accumulation between Day and Day 4 8

10 Study CTRV-CMX-20; TFV Pharmacokinetics DAY 28 5 mg 0 mg 25 mg 50 mg 00 mg Viread n n=2 n=9 n=0 n=0 n=0 n=8 Cmax [ng/ml] ( -- ) (0.5) (.5) (2.0) () (97.8) Tmax [h] Median (min, max) AUC 0-24 [ng-h/ml] t ½ [h] ( 6, 6) 23.4 ( -- ) 2 ( -- ) (2.5, 6) 28.8 (9.6) 23. (28.5) (4, 2) 63.7 (22.5) 23 (5.5) 4.0 (2.5, 0) 36 (33.3) 23.3 (3.4) (3, 0) 302 () 28. (7.2) (0.5, 2) 2690 (575) 8.7 (2.9) Approximately dose proportional PK with numerical increase at 00 mg Supports QD dosing No accumulation between Day and Day 4 Low levels of free TFV compared to Viread Mean (SD) for all except Tmax 9

11 Exposures in Healthy vs. HBV-infected Subjects A U C (0-2 4 ) n g.h /m L A U C (0-2 4 ) n g.h /m L D o s e v e r s u s S te a d y -S ta te A U C fo r T X L, D o s e v e r s u s S te a d y -S ta te A U C fo r T F V, S tu d y 0 2 a n d 2 0 S tu d y 0 2 a n d T X L, 2 0 S tu d y T F V, 2 0 S tu d y T X L, 0 2 S tu d y A re th e s lo p e s e q u a l? P = N ot significant T F V, 0 2 S tu d y A re the slopes equal? P = N ot significant D o s e o f T X L (m g ) D o s e o f T X L (m g ) AUC 0-24h of TXL across all doses tested was not statistically different in healthy vs. HBV-infected subjects AUC 0-24h of TFV TXL across all doses tested was not statistically different in healthy vs. HBV-infected subjects AUC 0-24h of TXL and TFV, at 00 mg, were numerically higher in HBVinfected subjects 0

12 Conclusions CMX57 and TFV exposures dose proportional from 0 to 00 mg without accumulation. PK in healthy and HBV-infected subjects comparable and supports QD dosing. Minimal food effect not clinically significant. Safe and well tolerated in healthy and HBV-infected subjects. No drug related safety signals. Low levels of circulating TFV may mitigate risk of kidney and bone toxicities associated with approved treatment. Data support continuing dose escalation to fully define CMX57 pharmacokinetics, safety and antiviral activity. Clinical investigation for HBV endpoints is ongoing.

13 Thank you Study subjects Clinical research sites and staff Siriraj Hospital, Mahidol University Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University Srinagarind Hospital, Khon Kaen University King Chulalongkorn University Hospital, Chulalongkorn University HIV-NAT, Bangkok Songklanagarind Hospital, Prince of Songkla University ACLIRES International Ltd. 2