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TNX-355, new HIV Drug, is Safe & Effective in Multiple Dose Phase 1 Study:
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Anti-CD4 Monoclonal Antibody in HIV-1-infected Subjects: Safety and Antiretroviral Activity of Multiple Doses
Reported by Jules Levin
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
TNX-355, a humanized IgG4 anti-CD4 domain 2 monoclonal antibodies, and showed potent anti-HIV-1 activity in vitro and in a phase 1a single-dose study in HAART-experienced subjects (CROI, 2003). The drug is administered by subcutaneous injection once weekly or perhaps less often.
TNX-355 is an attachment inhibitor that targets host CD4 receptors. It was selected to minimize chances for CD4 depletion by antibody- and complement-mediated toxicity. The study described below is to evaluate safety and efficacy of multiple doses in treatment-experienced patients. Clearly, this drug is aimed for patients willing to receive intravenous administration once weekly or perhaps every two weeks and most likely for patients with extensive HIV drug resistance. Administration can be conducted in doctor’s office. If the drug completes development & is FDA approved it could be administered in the home by a visiting nurse weekly or every other week.
It is administered intravenously weekly or biweekly in study and this may be enough to block HIV entry. Adverse events were mostly mild. A phase II study of TNX-355 in combination with optimized background therapy is planned for 2004.
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/uL.
Patients were randomized between 2 cohorts received TNX-355 for 9 weeks:
--cohort A (10 mg/kg/7 days)
--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.
Baseline Characteristics
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Weekly Biweekly
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Biweekly Hi-Dose arm
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Total
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N=9
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n=10
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N=3
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n=22
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Median age
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39
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42
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42
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41
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Female
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1
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1
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1
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3
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Mean Cd4 count
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313
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352
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390
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Mean HIV RNA (log)
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4.82
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4.84
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4.93
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Sensitivity to TNX-355:
--Env genes from 17/20 subjects amplified
--all were susceptible to TNX-355 at baseline
--21 subjects were ART-experienced (1 naïve)
--6 were failing
--15 on no current ART
RESULTS
Virtually all patients 21/22 had at least 0.5 log reduction in viral load. Many of patients had at least 1.0 log reduction.
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Mean Basel
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N
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No of Subj w/VL decrease
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VL (log)
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0.5
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0.75
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1.0
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1.20
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1.40
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Weekly
--10mg/kg Q wk
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4.77
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9
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9
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9
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7
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4
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2
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Biweekly
--10 mg/kg loading dose% 6 mg/kg Q 2 wks
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4.75
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10
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10
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7
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5
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4
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2
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Biweekly Hi-dose --25 mg/kg Q 2 wks
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4.89
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3
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2
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2
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2
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2
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1
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total
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4.78
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22
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21
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18
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14
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10
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5
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100%
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--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%; 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 baseline in CD4+ cell counts for cohorts A, B, and C were +257, +198 and +103 cells/uL, 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 (2) in same person with history of depression; suicidal ideation after 4th dose; 2nd episode after dose 8.
--New-onset grand mal seizure after vaso-vagal reaction during phlebotomy
--transient acute renal failure with known renal insufficiency requiring dialysis: developed 38 days after final dose in subject with renal insufficiency with proteinuria and chronic hyponatremia; renal function returned to baseline after hydration and discontinuation of NSAID
--there was 1 injection site reaction: infusion is into subcutaneous tissue
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