DMP-450 is the codename for an experimental anti-HIV drug that was discovered by DuPont Pharma and developed by Triangle Pharmaceuticals. DMP-450 is also known as mozenavir.

Anti-HIV drugs reduce the amount of virus in the body, thus slowing or preventing damage to the immune system. Preserving the immune system reduces the likelihood of AIDS-related illness in people with HIV.

DMP-450 belongs to the class of anti-HIV drugs known as protease inhibitors (PIs) the family of drugs which include indinavir, ritonavir, nelfinavir and saquinavir. DMP-450 is a new form of protease inhibitor known as a cyclic urea. Another experimental drug called BMS-232632 is also a cyclic urea protease inhibitor.

In January 2002, Triangle Pharmaceuticals admitted that it had no further plans to develop DMP-450 as a once daily protease inhibitor, despite its comparability with indinavir in a Phase III study (Sierra-Madero). DMP-450s future is now uncertain; despite promising results, the drug cannot be boosted with ritonavir, does not appear to carry a reduced risk of metabolic disturbances and is not active against virus already resistant to ritonavir or indinavir.

Current research

Phase I studies of an earlier compound, DMP-323, found that its absorption into the body was unpredictable. It was discontinued in favour of DMP-450, which is absorbed well in human and animal studies.

A Phase I/II study of DMP-450 or indinavir, in combination with d4T and 3TC, found no difference in viral load suppression between the two drugs after 12 weeks, but people who received indinavir were more likely to have experienced a significant increase in total serum cholesterol. At week 12, the highest dose of DMP-450 (1250mg tid) resulted in an average viral load decline of -3.12 log, compared to -2.41 log at a dose of 1250mg twice daily.

After 48 weeks, DMP-450 1250mg twice daily showed equivalence to three times daily dosing of DMP-450 or indinavir; by intent-to-treat (missing equals failure) analysis approximately 70% in each group had viral load below 400 copies at week 48.

Side-effects

DMP-450 also showed a lower rate of cholesterol elevation than indinavir; less than 20% of DMP-450 recipients at all doses had cholesterol elevations, compared to 56% of indinavir recipients. A higher incidence of neutropenia was reported among people taking DMP-450 1250mg twice daily compared to people taking indinavir or DMP-450 three times daily.

The development of DMP-450 was under review due to safety concerns, after animal studies showed signs of disturbances in electrical impulses in the heart (QT prolongation), but no difference in QT scores between individuals randomised to mozenavir or to indinavir was found in a 48 weeks study.

Dosage and interactions

The drug is likely to be dosed as one tablet twice daily, although this remains to be confirmed.

DMP-450 is unusual among protease inhibitors in that its metabolism is not inhibited by other PIs, preventing the possibility of boosting its plasma levels by dosing with ritonavir, a dosing strategy being pursued with some other protease inhibitors such as tipranavir.

The lowest concentration of DMP-450 in the body (the C_min) is approximately ten times higher than the concentration needed to inhibit HIV replication by 90% (the IC⁹⁰), suggesting that drug concentrations may not be a problem with DMP-450. However, the impact of drug resistance on the antiviral efficacy of DMP-450 is not known at this stage.

Resistance

Resistance mutations associated with prior indinavir or ritonavir treatment (at codons 82 and 84) are associated with reduced sensitivity to DMP-450, suggesting that this compound may not have great value as a salvage agent for multi-PI experienced individuals (Ala).

References

Ala PJ et al. Molecular basis of HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with cyclic urea inhibitors. Biochemistry 36(7): 1573-80, 1997.

Hodge CN et al. Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chemistry and Biology 3(4):301-314, 1996.

Sierra-Madero J et al. Antiviral activity, safety and pharamacokinetics of mozenavir (DMP 450). A novel cyclic urea protease inhibitor, in combination with d4T and 3TC in treatment naﶥ HIV-1 infected patients. First International AIDS Society Conference on HIV Pathogenesis and Treatment, Buenos Aires, abstract 2, 2001.