Nuevos fármacosf. Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona

Transcription

1 Nuevos fármacosf Pere Domingo Malalties Infeccioses Hospital de la Santa Creu i Sant Pau Barcelona pdomingo@santpau.cat

2 Fármaco Compañí ñía Familia Nº abstract GS-7340 Gilead ITIAN 152LB GSK GSK ITINAN 520, 628, 631 Cenicriviroc Takeda Pharm CCR5 54LB VIRIP MHH Inh. entrada 58LB Ibalizumab ADCAR AcAnti-CD4 585 BMS BMS Inh. unión 487 BMS BMS Inh. unión 518 BMS BMS Inh. unión 588

3 Fármaco Compañí ñía Familia Nº abstract GS-7340 Gilead ITIAN 152LB GSK GSK ITINAN 520, 628, 631 Cenicriviroc Takeda Pharm CCR5 54LB VIRIP MHH Inh. entrada 58LB Ibalizumab ADCAR AcAnti-CD4 585 BMS BMS Inh. unión 487 BMS BMS Inh. unión 518 BMS BMS Inh. unión 588

4 GS-7340

5 GS-7340 Demonstrates Greater Declines in HIV-1 RNA than Tenofovir Disoproxil Fumarate During 14 Days of Monotherapy in HIV-1 Infected Subjects M Markowitz, 1 A Zolopa, 2 * P Ruane, 3 K Squires, 4 L Zhong, 5 BP Kearney, 5 and W Lee 5 1 Aaron Diamond AIDS Research Center, New York, NY; 2 Stanford University Positive Care Clinic, Palo Alto, CA; 3 Lighthouse Medical, Los Angeles, CA; 4 Thomas Jefferson University, Philadelphia, PA; 5 Gilead Sciences, Foster City, CA 18 th Conference on Retroviruses and Opportunistic Infections March 2, 2011 Paper # 152LB

6 Introduction GS-7340 is a novel amidate prodrug that was designed to deliver high concentrations of tenofovir diphosphate to lymphoid cells The targeted delivery to lymphatic tissue should allow for a low dose and minimal systemic levels of tenofovir Chronic safety studies in dogs and rats demonstrate a greater therapeutic index relative to TDF M Markowitz, et al., CROI 2011; Paper # 152LB.

7 GS-7340: Targeting Lymphoid Cells O P HO OH O N N NH 2 N N O O O O O P O O O O O Tenofovir TDF GS-7340 N N NH 2 N N O O O P N H O O N N NH 2 N N EC 50 HIV-1 (PBMCs) 1.2 µm µm µm GS-7340 is 400-fold more potent than tenofovir in PBMCs 1 GS-7340 is 200-fold more stable in plasma than TDF resulting in circulating levels of prodrug 1 GS-7340 is rapidly metabolized inside the lysosomes of lymphoid cells by the enzyme cathepsin A 2 M Markowitz, et al., CROI 2011; Paper # 152LB. 1 Lee et al. Antimicrob Agents Chemother Birkus et al. Antimicrob Agents Chemother 2007

8 Increased Distribution to PBMCs In Vivo Plasma to PBMC ratio following administration of TFV, TDF or GS-7340 to dogs (10 mg-eqv/kg) 1 1:140 c 1:1.4 1:5 Subcut. Oral M Markowitz, et al., CROI 2011; Paper # 152LB. 1 Lee et al. Antimicrob Agents Chemother 2005

9 Objectives Primary Objectives To evaluate the antiviral potency of 2 different doses of GS-7340 as compared to TDF Primary endpoint: DAVG at Week 2 To determine the safety of GS-7340 over 14 days Secondary Objectives To determine the plasma and intracellular PK of GS-7340 To determine the viral dynamics of HIV-1 RNA in plasma M Markowitz, et al., CROI 2011; Paper # 152LB.

10 Study Design HIV-1-infected adults ART Treatment-naïve HIV-1 RNA 15,000 c/ml CD4 count 200 cells/mm 3 Randomized, double-blind 3 arm study TDF 300 mg (active control arm) GS mg GS mg Monotherapy for 14-day once-daily dosing M Markowitz, et al., CROI 2011; Paper # 152LB.

11 Baseline Characteristics TDF 300mg (N=10) GS mg (N=10) GS mg (N=10) Age (mean) 34.8 ± ± ± 6.5 Sex (males) Ethnicity Caucasian Black Latino Asian Mean HIV-1 RNA (log 10 copies/ml) 5.03 ± ± ± 0.30 Mean CD4 cell count 384 ± ± ± 108 M Markowitz, et al., CROI 2011; Paper # 152LB.

12 Primary Efficacy Endpoint Treatment (10 pts/arm) TDF 300 mg GS mg GS mg Mean DAVG 2 [log 10 c/ml] ± ± ± 0.14 p-value vs. TDF 300 mg M Markowitz, et al., CROI 2011; Paper # 152LB.

13 Viral Dynamics Treatment (10 pts/arm) Mean VL Day 14 [log 10 c/ml] p-value of mean VL vs. TDF 300 mg Mean first phase decay slope p-value of mean decay slope vs. TDF 300 mg TDF 300 mg ± ± GS mg ± ± GS mg ± ± M Markowitz, et al., CROI 2011; Paper # 152LB.

14 Viral Dynamics Viral Load from Baseline (log 10 c/ml) TDF 300 mg GS mg GS mg Day M Markowitz, et al., CROI 2011; Paper # 152LB.

15 Tenofovir Levels in Plasma: PK Profile on Day Tenofovir in plasma [ng/ml] AUC 0-24h 56%* 88%* TDF 300 mg GS mg GS mg * p-value <0.001 Hours M Markowitz, et al., CROI 2011; Paper # 152LB.

16 Tenofovir Diphosphate in PBMCs 10 33x Tenofovir-DP in PBMCs [um] 1 8x 18x* 4x * TDF 300 mg GS mg GS mg 0.1 Day 3 Day 14 * p-value <0.05 M Markowitz, et al., CROI 2011; Paper # 152LB.

17 Safety and Resistance No dose interruptions or discontinuations No serious adverse events No clinically significant laboratory abnormalities Most frequent adverse events were mild to moderate headache and nausea No resistance mutations to GS-7340 or TDF were detected at day 14 in any subject M Markowitz, et al., CROI 2011; Paper # 152LB.

18 Summary Monotherapy with GS-7340 at 50 or 150 mg led to significantly greater decreases in HIV-1 RNA and at lower systemic tenofovir exposures than with TDF 300 mg GS-7340 is a next generation oral prodrug of tenofovir that has the potential to improve upon the efficacy and safety of TDF for the treatment of HIV The lower dose of GS-7340 will permit the development of new single tablet regimens that are not possible today GS-7340 has the potential of making tenofovir more widely available in resource limited settings given the relative manufacturing expense compared to TDF M Markowitz, et al., CROI 2011; Paper # 152LB.

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35 Infusión n de CD4 autólogos R5/X4- defectivos

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53 Creating HIV-resistant CD4+ T cells with CXCR4- zinc finger nucleases Craig Wilen Lab of Robert Doms University of Pennsylvania

54 Long term-goal: recapitulate the Berlin patient by genome editing the HIV coreceptor genes Adoptive therapy phase I trial with CCR5-ZFNs is currently underway. ~50% of ART-experienced individuals have R5X4 or X4 HIV. CXCR4-ZFNs may protect against X4 HIV and can be combined with CCR5-ZFNs treatment to create completely HIV-resistant CD4+ T cells. By disrupting CXCR4 in CD4+ T cells we avoid toxicities associated with systemic disruption.

55 X4-ZFNs specifically bind, cleave, and disrupt the cxcr4 gene

56 CXCR4-ZFNs efficiently disrupt cxcr4 in CD4+ T cells and do not adversely affect cell growth Ad5/F35 X4-ZFN Ad5/F35 GFP

57 The most common CXCR4 mutation is an in-frame deletion that does not traffic to the cell surface 80% of mutations are deletions. In-frame deletions occur 2.5 fold more frequently than predicted. An 18bp deletion, CXCR4 18, is the most common mutation and does not traffic to the cell surface. Sean Patro

58 X4-ZFN treatment of CD4+ T cells preserves cell growth and viability in the presence of HIV Mock HIV Bk132: Primary X4 HIV Cumulative live cell count HxB: Lab adapted X4 HIV R3A: Primary dual tropic HIV NTD R5ZFN X4ZFN Time (days)

59 Survival advantage in the presence of HIV is due to CXCR4 disruption 19 days post infection

60 CXCR4 disruption confers protection from X4 HIV in humanized mice X4-ZFNs conferred protection by 14 dpi, but this effect waned over time. Evolution or outgrowth of preexisting R5X4 HIV observed in X4- ZFN but not R5-ZFN-treated mice.

61 Conclusions CXCR4-ZFNs specifically and efficiently disrupt CXCR4. X4-ZFNs confer robust protection of CD4+ T cells from X4 HIV challenge in vitro. CXCR4 disruption confers protection from X4 HIV in humanized mice, resulting in outgrowth of R5X4 HIV. Future studies aim to combine CCR5- and CXCR4-ZFNs to eliminate HIV coreceptor expression.

62 La crisis se produce cuando lo viejo no acaba de morir y cuando lo nuevo no acaba de nacer Bertolt Brecht ( ) 1956)