TMB-355(Ibalizumab) is a humanized monoclonal antibody (mAb) and a member of an emerging class of HIV therapies known as viral-entry inhibitors. This drug candidate is distinct from other entry inhibitors in that it binds to the CD4 molecule, the primary receptor for HIV infection, thereby interfering with the penetration of the virus into the cell. It is the first entry-blocking humanized mAb to treat HIV/AIDS. TMB-355 caught the attention of the scientific community in February 2003, when results from the phase-1, single-dose clinical trial showed a transient but clinically significant reduction in the patients’ viral load. Moreover, it was well tolerated with no evidence of adverse effects on CD4 T-cells of treated subjects unlike the majority of approved drugs for HIV. The U.S. FDA granted TMB-355 fast track status in October 2003. The phase-2a clinical trial was successfully completed in 2006, with the results showing a clean safety profile and clear antiviral activity (10-fold reduction in viral load). The Phase-2b clinical trial was also successfully completed in 2011. TaiMed Biologics is concurrently developing a subcutaneous injection dosage form and a phase 1 human pharmacokinetics bridging study is completed in 2012. Currently, TMB is developing a phase I/II study for HIV-negative and new HIV-positive subjects to begin by the end of 2012.
|Phase 2a Study Design and Results
The phase 2a study is a multi-center, randomized, double-blind, placebo-controlled trial to compare safety and efficacy of two doses of TMB-355 against placebo among F82 treatment-experienced HIV positive patients. TMB-355 in combination with OBR (optimized background regimen) resulted in statistically significant viral load reduction compared to placebo plus OBR. Dosing at 10 mg/kg led to a decrease in viral load was associated with a statistically significant and clinically meaningful increase in CD4+ T cells. TMB-355 was well tolerated with no infusion-site reactions, no serious adverse events, and no laboratory abnormalities. In addition, good patient adherence to study visits and acceptance of intravenous administration were observed.
Phase 2b Clinical Trial
A 113-patient Phase 2b clinical trial was completed in January 2011. The primary evaluation of effectiveness will be based on the proportion of patients achieving undetectable viral loads at week 24. Secondary objectives include evaluation of changes in viral load, CD4+ cell counts, TOLVR, PK sensitivity, susceptibility and safety.
Phase 2b Study Clinical Outcomes (Virologic Endpoints, ITT-MEF)
|Arm||800mg q2w||2000mg q4w||Overall|
|Dosage and Regimens||One Injection Per 2 Weeks，Used 800mg TMB-355
(800mg /2 weeks)
|One Injection Per 2 Weeks， Used 2000mg TMB-355 or Vehicle Alternately
(2000mg /4 weeks)
|800mg /2 weeks or 2000mg /4 weeks|
|No. of Subjects (N)||59||54||113|
|% of Subjects with Viral Load < 400 copies/ml (%＜400)||58||46||52|
|% of Subjects with Viral Load < 200 copies/ml (%＜200)||53||43||48|
|% of Subjects with Viral Load < 50 copies/ml (%＜50)||44||28||36|
|% of Subjects with Viral Load Reduced by 90% Above (%≧1 log drop)||63||59||60|
|Mean; Log10 change from baseline||-1.6||-1.5||-1.5|
|Median; Log10 change from baseline||-1.8||-1.5||-1.6|
Phase 2b Clinical Study The Most Frequent (4% above) Adverse Reaction
Subcutaneous injection dosage form
TaiMed has another subcutaneous (s.c.) injection dosage form under development. The s.c. dosage will allow the patients to inject under the skin by themselves. The dosage form has the potential to apply only once weekly or monthly. It would promote convenience of using TMB-355. The phase I clinical trial study of the subcutaneous dosage started in November 2010 at six hospitals/clinics in United States. The future phase II clinical trial study is already fully funded by the Bill & Melinda Gates Foundation。
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