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TMB-607 (formerly coded PPL-100 by Ambrilia and MK-8122 by Merck) is a novel HIV-1 protease inhibitor and was initially developed by Ambrilia Biopharma Inc. TaiMed entered into global licensing agreement with Ambrilia Biopharma Inc. in 2011 and then acquired the investigational compounds for anti HIV-1 investigational use in 2012.
TMB-607 displays a robust resistance profile and maintains activity against HIV with multiple primary protease inhibitor mutations which are known to confer resistance to currently marketed drugs. This indicates a very high genetic barrier for resistance to TMB-607. Moreover, single mutations arising in the presence of TMB-607 do not reduce susceptibility to TMB-607, and while a unique quadruple mutation pattern will result in mild resistance to TMB-607, these mutants remain sensitive (or even hypersensitive in some cases) to approved protease inhibitors.
Long-acting parenteral antiretroviral treatment to HIV
Although available antiretroviral regimens do not provide a cure for HIV, the disease has become a chronic disease requiring lifelong daily oral treatment. However, patients with poor adherence to daily oral medications is common. An estimates of nonadherence in 50-75% over time was reported , thus leads the drug exposure insufficient to suppress HIV viral replication, and increases the likelihood for emergence of resistance. Therefore, long-acting parenteral formulations have potential to replace the daily pill by taking with frequency injection. A survey indicated that 61% of patients would try the long-acting antiretroviral parenteral treatment if it was as frequently as once per week and 84% with once-monthly dosing .
TaiMed developed a novel HIV-1 protease inhibitor (TMB-607), using a proven nanotechnology formulation for subcutaneous and/or intramuscular injections. At least 100 folds reduction in particle size led TMB-607 molecule in a nano-scale range (see below figure). The nanonized TMB-607 nanosuspension would increase the dissolution rate of TMB-607 in aqueous solutions, thus enhancing its bioavailable in human body, decreasing the drug consumption and the medical cost compared to daily oral pill. Therefore, use of parenterally administered of long-acting TMB-607 nanosuspension may provide patients with the convenience of infrequent dosing, reduced gastrointestinal toxicities, and improved tolerability relative to orally administered current protease inhibitors (PIs).
Preliminary study showed that long-acting drug exposures for more than 1 month in rats, dogs and monkeys after single subcutaneous or intramuscular injection of TMB-607 nanosuspensions were observed. These results indicated that TMB-607 nanosuspension has high potential with monthly treatment for HIV patients.
1. Coleman CI, Roberts MS, Sobieraj DM, et al. Effect of dosing frequency on chronic cardiovascular disease medication adherence. Curr Med Res Opin 2012; 28:669–680.
2. Jennifer W, Harlan RS, Jane LM, et al. Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine 2013; 8: 1807-1813.