Home Search Abstracts Browse Sessions Program Committee E-mail Abstract Author View Session

Session 78 Poster Abstracts
New Antiretroviral Agents: Entry Inhibitors
Wednesday, 1:30 - 3:30 pm
Poster Hall


536
Phase 1b Study of the Anti-CD4 Monoclonal Antibody TNX-355 in HIV-1-infected Subjects: Safety and Antiretroviral Activity of Multiple Doses
J M Jacobson*1, D R Kuritzkes2, E Godofsky3, E DeJesus4, S Lewis5, J Jackson6, K Frazier6, E A Fagan6, and W R Shanahan6
1Beth Israel Med. Ctr., New York, NY, USA; 2Brigham and Women's Hosp., Boston, MA, USA; 3Bach & Godofsky, Bradenton, FL, USA; 4IDC Res. Initiative, Altamonte Springs, FL, USA; 5Univ. of Texas Hlth. Sci. Ctr., Houston, USA; and 6Tanox, Inc., Houston, TX, USA

Background:  TNX-355, a humanized IgG4 anti-CD4 domain 2 monoclonal antibodies, showed potent anti-HIV-1 activity in vitro and in a phase 1a single-dose study in HAART-experienced subjects (CROI, 2003).

Methods:  TNX-355 was added as a single new drug to unchanged ART or none for ≥2 months in 22 HIV-1-infected subjects with stable baseline viral loads of ≥5000 copies/mL and CD4+ cell counts ≥100/μL.19 randomized between 2 cohorts received TNX-355 for 9 weeks:  dohort A (10 mg/kg/7 days) and cohort B (6 mg/Kg/14 days after 10 mg/kg loading dose). Cohort C (3 subjects; 25 mg/kg/14days; 8 weeks) was added to enable higher doses in phase 2.

Results:  Of the total, 21 subjects were ART-experienced (1 naïve); 6 were falling, and 15 on no current ART. Baseline mean log10 viral loads (4.78; range 3.7 to 5.9) and CD4+ cells (332/μL; range 89 to 494) were similar across cohorts. Mean peak decreases from baseline in log10 viral loads of 0.99, 1.11 and 0.96 occurred by week 2 in cohorts A, B and C, respectively. Log10 viral loads decreased by >1.0 in 64% (Table 1); 4 to ≤400 copies/mL. Viral loads returned towards baseline by week 9 with reduced susceptibility (increase in IC50) to TNX-355 (Phenosense assay; Virologic, Inc.). CD4+ cells rose transiently and fluctuated above and below baseline during and after dosing. Maximum median elevations above base;ome in CD4+ cell counts for cohorts A, B, and C were +257, +198 and +103 cells/μL, respectively and occurred within 3 weeks in 16 of 22 subjects. TNX-355 CD4 cell coating was complete for cohorts A and C through ≥2 weeks beyond final dosing. Cohort B had intermittent CD4+ cell coating. Serious adverse events (3) were recurrence of known depression, new-onset seizure after vaso-vagal reaction during phlebotomy and acute renal failure with known renal insufficiency.

 

Maximum reduction in Log10VL during dosing ( 9 Weeks)

Cohort

Dose

Mean BL Log10VL

 

N

No. of Subjects with Log10 VL Decrease from BL

≥0.5

≥0.75

≥1.0

≥1.20

≥1.40

A

10 mg/kg each week

4.77

9

9

9

7

4

2

B

10 mg/kg loading dose, 6 mg/kg every 2 weeks

4.75

10

10

7

5

4

 2

C

25 mg/kg every 2 weeks

4.89

3

2

2

2

2

1

 

Total No. (%)

 

4.78

22

(100)

21 (95)

   18

  (82)

14

(64)

10

(45)

5

(23)

 

Conclusions:  Multiple-dose TNX-355 added as a single new agent, showed transient but clinically meaningful reductions (0.5-1.7 log10) in HIV RNA in 21 of 22 subjects. Return towards Baseline in viral load occurred with reduced susceptibility to TNX-355. TNX-355 was well tolerated. A phase 2 study of TNX-355 in combination with OBT in ART-experienced subjects is planned.

 

Keywords: TNX-355; anti-CD4; entry-inhibitor